Compounds

ABSTRACT

The present invention relates to novel compounds that inhibit Lp-PLA2 activity, processes for their preparation, to compositions containing them and to their use in the treatment of diseases associated with the activity of Lp-PLA2, for example Alzheimer&#39;s disease.

RELATED APPLICATION

The present application claims priority from PCT InternationalApplication No. PCT/CN2014/000695 filed on Jul. 22, 2014 at the StateIntellectual Property Office of the People's Republic of China, theentire contents of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to novel tricyclic imidazo-pyrimidinonecompounds, processes for their preparation, intermediates useful intheir preparation, pharmaceutical compositions containing them, andtheir use in therapy for the treatment of diseases mediated by Lp-PLA₂.

BACKGROUND OF THE INVENTION

Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) previously known asplatelet-activating factor acetylhydrolase (PAF-AH), is a phospholipaseA2 enzyme involved in hydrolysis of lipoprotein lipids or phospholipids.Lp-PLA₂ travels with low-density lipoprotein (LDL) and rapidly cleavesoxidized phosphatidylcholine molecules derived from the oxidation ofLDL. (See e.g., Zalewski A, et al., Arterioscler. Thromb. Vasc. Biol.,25, 5, 923-31(2005)). Lp-PLA₂ hydrolyzes the sn-2 ester of the oxidizedphosphatidylcholines to give lipid mediators, lyso-phosphatidylcholine(lysoPC) and oxidized nonesterified fatty acids (NEFAs). It has beenobserved that lysoPC and NEFAs elicit inflammatory responses. (See e.g.,Zalewski A, et al. (2005)).

A number of Lp-PLA₂ inhibitors and/or uses thereof have been previouslydescribed. (See. for example, published patent application nos.WO96/13484, WO96/19451, WO97/02242, WO97/12963, WO97/21675, WO97/21676,WO 97/41098, WO97/41099, WO99/24420, WO00/10980, WO00/66566, WO00/66567,WO00/68208, WO01/60805, WO02/30904, WO02/30911, WO03/015786,WO03/016287, WO03/041712, WO03/042179, WO03/042206, WO03/042218,WO03/086400, WO03/87088, WO08/048867, US 2008/0103156, US 2008/0090851,US 2008/0090852, and WO08/048866.) Disclosed uses include treatingdisease that involves or is associated with endothelial dysfunction,disease that involves lipid oxidation in conjunction with Lp-PLA₂activity (e.g., associated with the formation of lysophosphatidylcholineand oxidized free fatty acids), and disease that involves activatedmonocytes, macrophages or lymphocytes or which is associated withincreased involvement of monocytes, macrophages or lymphocytes. Examplesof diseases include atherosclerosis (e.g. peripheral vascularatherosclerosis and cerebrovascular atherosclerosis), diabetes,hypertension, angina pectoris, after ischaemia and reperfusion,rheumatoid arthritis, stroke, inflammatory conditions of the brain suchas Alzheimer's Disease, various neuropsychiatric disease such asschizophrenia, myocardial infarction, ischaemia, reperfusion injury,sepsis, acute and chronic inflammation, and psoriasis.

Lp-PLA₂ inhibitors and/or uses thereof are also reported, for example,in PCT Publication Nos. WO05/003118 (and its Canadian family member CA2530816A1); WO06/063811; WO06/063813 and WO 2008/141176; JP 200188847;and US Published Patent Application Nos. US 2008/0279846 A1, US2010/0239565 A1, and US 2008/0280829 A1.

Other researchers have studied the effects related to Lp-PLA₂ andinhibitors thereof. For example, research data has also indicated thatLysoPC promotes atherosclerotic plaque development, which can ultimatelylead to the formation of a necrotic core. (See e.g., Wilensky et al.,Current Opinion in Lipidology, 20, 415-420 (2009)). In addition, theeffect of Lp-PLA₂ inhibitors on atherosclerotic plaque composition wasdemonstrated in a diabetic and hypercholesterolemic porcine model ofaccelerated coronary atherosclerosis. (See e.g., Wilensky et al., NatureMedicine, 10, 1015-1016 (2008)). These research results provided furtherevidence that Lp-PLA₂ inhibitors may be used to treat atherosclerosis.

Additional studies indicate that high Lp-PLA₂ activity is associatedwith high risk of dementia, including Alzheimer's disease (AD) (Seee.g., Van Oijen, et al. Annals of Neurology, 59,139 (2006)). Higherlevels of oxidized LDL have also been observed in AD patients (See e.g.,Kassner et al. Current Alzheimer Research, 5, 358-366 (2008); Dildar, etal., Alzheimer Dis Assoc Disord, 24, April-June (2010); Sinem, et al.Current Alzheimer Research, 7, 463-469 (2010)). Further, studies showthat neuroinflammation is present in AD patients and multiple cytotoxicinflammatory cytokines are up-regulated in AD patients. (See e.g.,Colangelo, et al., Journal of Neuroscience Research, 70, 462-473 (2002);Wyss-Coray, Nature Medicine, 12, September (2006)). Research has shownthat LysoPC function is a pro-inflammatory factor inducing multiplecytotoxic inflammatory cytokine release (See Shi, et al.Atherosclerosis, 191, 54-62 (2007)). Therefore, these studies provideadditional evidence that that the inhibitors of Lp-PLA₂ can be used totreat AD by inhibiting activity of Lp-PLA₂ and reducing lysoPCproduction.

In addition, use of an Lp-PLA₂ inhibitor in a diabetic andhypercholesterolemia swine model demonstrated that blood-brain-barrierleakage and brain amyloid beta protein (Aβ) burden, the pathologicalhallmarks of Alzheimer's disease, were reduced. (See U.S. PatentApplication Publication No. 2008/0279846). This publication describesseveral uses of Lp-PLA₂ inhibitors for treating diseases associated withblood-brain-barrier leakage, including, e.g., Alzheimer's disease andvascular dementia.

Further, neuroinflammation, including multiple cytotoxic cytokinerelease, is a common feature of all neurodegenerative diseases includingmultiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease,Alzheimer's disease, etc. (See e.g., Perry, Acta Neuropathol, 120,277-286 (2010)). As discussed above, Lp-PLA₂ inhibitors can reduceinflammation, for example, reducing multiple cytokine release bysuppressing lysoPC production. (See e.g., Shi, et al. Atherosclerosis191, 54-62 (2007)). Thus, inhibiting Lp-PLA₂ is a potential therapeutictreatment for neurodegenerative diseases including multiple sclerosis,amyotrophic lateral sclerosis, Parkinson's disease, etc.

In addition to the inflammatory effect, LysoPC has been implicated inleukocyte activation, induction of apoptosis and mediation ofendothelial dysfunction (See, e.g., Wilensky et al., Current Opinion inLipidology, 20, 415-420 (2009)). Therefore, it is believed that Lp-PLA₂inhibitors can be used to treat tissue damage associated with diabetesby reducing the production of lysoPC, which can cause a continuous cycleof vascular inflammation and increased reactive oxygen species (ROS)production. In light of the inflammatory roles of Lp-PLA₂ and theassociation between localized inflammatory processes and diabeticretinopathy, it is postulated that Lp-PLA₂ can be used to treat diabeticocular disease.

Glaucoma and age-related macular degeneration (AMD) are retinaneurodegenerative diseases. Studies suggest that inflammation, includingTNF-alpha signaling, may play an important role in the pathogenesis ofglaucoma and AMD (See e.g., Buschini et al., Progress in Neurobiology,95, 14-25 (2011); Tezel, Progress in Brain Research, vol. 173,ISSN0079-6123, Chapter 28). Thus, considering Lp-PLA₂ inhibitors'function of blocking inflammatory cytokine release (See e.g., Shi, etal. Atherosclerosis, 191, 54-62 (2007)), it is believed that Lp-PLA₂inhibitors can provide a potential therapeutic application for bothglaucoma and AMD.

In view of the number of pathological responses that are mediated byLp-PLA₂, attempts have been made to prepare compounds that inhibit itsactivity. Though a number of such compounds have been disclosed in theart, there remains a continuing need for inhibitors of Lp-PLA₂ which canbe used in the treatment of a variety of conditions.

SUMMARY OF THE INVENTION

In a first aspect, this invention relates to compounds of Formula (I-1)and salts (e.g., pharmaceutically acceptable salts) thereof,

wherein

-   -   R¹ is selected from the group consisting of H, C₁₋₃alkyl and        —C(O)—C₁₋₃alkyl; and    -   R² and R³ together with the carbon to which they are attached        form a 4, 5 or 6 membered saturated ring, which ring        -   optionally contains one heteroatom ring member selected from            N or O, and        -   is optionally substituted with one substituent of -L-K,            wherein            -   L is selected from the group consisting of C(O), CH₂,                and S(O)₂, and            -   K is selected from the group consisting of C₁₋₃alkyl,                phenyl, and C₃₋₆cycloalkyl;    -   or R¹ and R² together with the nitrogen and carbon to which they        are attached form a 5 or 6-membered heterocyclic saturated ring,        which ring        -   optionally contains one or two additional heteroatom ring            member independently selected from the group consisting of            N, O, C(O), S, S(O), and S(O)₂, and        -   is optionally substituted with one or more substituents            independently selected from the group consisting of OH,            halo, NR^(1a)R^(1b), COOH, and —Y—R^(c), wherein            -   Y is absent or is selected from the group consisting of                C(O), S(O)₂, —C(O)—C(O)—, and CH₂, and            -   R^(c) is selected from the group consisting of                -   C₁₋₅alkyl optionally substituted with one or more                    substituents independently selected from the group                    consisting of NR^(2a)R^(2b), C₃₋₆ cycloalkyl, and                    —COOH,                -   C₁₋₃haloalkyl,                -   C₁₋₃alkoxyl,                -   NR^(3a)R^(3b),                -   —(CH₂)_(p)—C(O)—O—C₁₋₃alkyl, wherein p is 1, 2, or 3                    and the —(CH₂)_(p)— is optionally substituted by one                    or more methyl,                -   —(CH₂)_(q)—C₃₋₆ cycloalkyl wherein q is 1, 2, or 3,                    wherein the cycloalkyl is optionally substituted                    with NR^(4a)R^(4b) and the —(CH₂)_(q)— is optionally                    substituted by one or more methyl, and                -   heterocyclyl optionally substituted with one or more                    substituents independently selected from the group                    consisting of halo and NR^(5a)R^(5b),        -   wherein R^(1a), R^(1b), R^(2a), R^(2b), R^(3a), R^(3b),            R^(4a), R^(4b), R^(5a), and R^(5b) are independently H or            C₁₋₃alkyl; and    -   R³ is H;    -   each occurrence of R⁴ is independently H or D;    -   X is absent or is selected from the group consisting of        -   —O—,        -   —NH—, and        -   —N—(C₁₋₃ alkyl)-,    -   n is 1 or 2;    -   or X is —O—CH₂— bicyclo[1.1.1]pentanyl-CH₂—O— and n is 0; and    -   A is unsubstituted thiophenyl, or    -   A is

wherein

-   -   R⁵ and R⁹ are independently H or halo,    -   Z′ is N or CR⁶,    -   Z is N or CR⁸,        -   wherein R⁶ and R⁸ are independently selected from the group            consisting of H, CN, halo, C₁₋₃alkyl, C₁₋₃haloalkyl,            —S(O)₂—C₁₋₃alkyl and —S(O)—C₁₋₃alkyl, and    -   V is N or CR⁷, wherein R⁷ is selected from the group consisting        of H, halo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, and —S(O)₂—C₁₋₃alkyl,        or R⁷ is -Q-(CH₂)_(m)—W,        -   wherein            -   Q is O, N, or CH₂,            -   m is 0 or 1, and            -   W is selected from the group consisting of C₃₋₆                cycloalkyl, heterocyclyl, 5 or 6 membered heteroaryl and                phenyl, wherein said cycloalkyl, heterocyclyl,                heteroaryl or phenyl is optionally substituted with one                or more substituents independently selected from the                group consisting of C₁₋₃haloalkyl, CN, halo and C₁₋₅                alkyl;    -   or when Z or Z′ is CR⁶ and V is CR⁷, R⁶ and R⁷ together may form        a 4,7-dioxaspiro[2.6]nonane;        with the proviso that the compound of Formula (I-1) is not

-   2-fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile,

-   7-(2,3-difluorophenethyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one,

-   7-((2,3-difluorobenzyl)amino)-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione,

-   7-((3,4-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one    2,2-dioxide,

-   7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one-2-oxide,

-   7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one-2,2-dioxide,

-   7-(2,3-difluorophenethyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one,

-   4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-spiro[cyclobutane-1,2′-imidazo[1,2-c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile,

-   4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-spiro[cyclopentane-1,2′-imidazo[1,2-c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile,    or

-   4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-spiro[cyclohexane-1,2′-imidazo[1,2-c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile.

This invention also relates to a pharmaceutical composition comprisingcompounds of this invention and a pharmaceutically acceptable excipient.

The invention also relates to methods of treating or preventing adisease associated with the activity of Lp-PLA₂, which comprisesadministering to a subject in need thereof with a therapeuticallyeffective amount of a compound of the invention described herein. Thedisease may be associated with the increased involvement of monocytes,macrophages or lymphocytes; with the formation oflysophosphatidylcholine and oxidized free fatty acids; with lipidoxidation in conjunction with Lp-PLA₂ activity; or with endothelialdysfunction.

This invention also provides methods of treating or preventing a diseaseby inhibiting Lp-PLA₂ activity. Exemplary diseases include, but are notlimited to, neurodegeneration disease (e.g., Alzheimer's disease,Parkinson's disease, Huntington's disease, vascular dementia),atherosclerosis, stroke, metabolic bone disorder (e.g., bone marrowabnormalities), dyslipidemia, Paget's diseases, type II diabetes,metabolic syndrome, insulin resistance, and hyperparathyroidism,diabetic ocular disorder (e.g., macular edema, diabetic retinopathy, andposterior uveitis), macular edema, wound healing, rheumatoid arthritis,chronic obstructive pulmonary disease (COPD), psoriasis, and multiplesclerosis. The methods comprise administering a therapeuticallyeffective amount of a compound of this invention to a subject in needthereof. It is not intended that the present invention is limited to anyparticular stage of the disease (e.g. early or advanced).

This invention also provides methods of treating or preventingAlzheimer's disease. The methods comprise administering to a subject inneed thereof a therapeutically effective amount of a compound of thisinvention.

This invention also provides methods of treating or preventingatherosclerosis. The methods comprise administering to a subject in needthereof a therapeutically effective amount of a compound of thisinvention.

This invention also provides methods of decreasing beta amyloid (alsoreferred to as “Aβ”) accumulation in the brain of a subject. The methodscomprise administering to a subject in need thereof a therapeuticallyeffective amount of a compound of the present invention. In certainembodiment, the beta amyloid is Abeta-42.

This invention also provides methods for treating or preventing oculardiseases by administering a compound of this invention. In certainembodiment, this invention provides methods of treating macular edema,which comprises administering to the subject a therapeutically effectiveamount of a compound of this invention. In certain embodiment, themacular edema is associated with diabetic ocular disease, for example,diabetic macular edema or diabetic retinopathy. In one embodiment, themacular edema is associated with posterior uveitis.

This invention also provides a use of compounds of this invention in themanufacture of a medicament for treating or preventing diseasesdescribed herein.

This invention also provides compounds of this invention for use in thetreatment or prevention described herein.

DETAILED DESCRIPTION OF THE INVENTION

As used in the description of the embodiments of the invention and theappended claims, the singular forms “a”, “an” and “the” are intended toinclude the plural forms as well, unless the context clearly indicatesotherwise. Also, as used herein, “and/or” refers to encompasses any andall possible combinations of one or more of the associated listed items.It will be further understood that the terms “comprises” and/or“comprising” when used in this specification, specify the presence ofstated features, integers, steps, operations, elements, and/orcomponents, but do not preclude the presence or addition of one or moreother features, integers, steps, operations, elements, components,and/or groups thereof.

Generally, the nomenclature used herein and the laboratory procedures inorganic chemistry, medicinal chemistry, biology described herein arethose well known and commonly employed in the art. Unless definedotherwise, all technical and scientific terms used herein generally havethe same meaning as commonly understood by one of ordinary skill in theart to which this disclosure belongs. In the event that there is aplurality of definitions for a term used herein, those in this sectionprevail unless stated otherwise.

A. Definitions

As used herein, unless otherwise indicated, “disease” refers to anyalteration in state of the body or of some of the organs, interruptingor disturbing the performance of the functions and/or causing symptomssuch as discomfort, dysfunction, distress, or even death to the personafflicted or those in contact with a person. A disease can also includea distemper, ailing, ailment, malady, disorder, sickness, illness,complaint, interdisposition and/or affectation.

As used herein, unless otherwise indicated, “neurodegeneration disease”as used herein refers to a varied assortment of central nervous systemdisorder characterized by gradual and progressive loss of neural tissueand/or neural tissue function. A neurodegeneration disease is a class ofneurological disease where the neurological disease is characterized bya gradual and progressive loss of neural tissue, and/or alteredneurological function, typically reduced neurological function as aresult of a gradual and progressive loss of neural tissue. In certainembodiments, the neurodegeneration diseases described herein includeneurodegeneration diseases where there is a defective blood brainbarrier, for example a permeable blood brain barrier. Examples ofneurodegeneration diseases where there is a defective blood brainbarrier include, but are not limited to, Alzheimer's disease,Huntington's disease, Parkinson's disease, vascular dementia and thelike.

As used herein, unless otherwise indicated, “vascular dementia” is alsoreferred to as “multi-infarct dementia”, which refers to a group ofsyndromes caused by different mechanisms, which all result in vascularlesions in the brain. The main subtypes of vascular dementia are, forexample, vascular mild cognitive impairment, multi-infarct dementia,vascular dementia due to a strategic single infarct, (affecting thethalamus, the anterior cerebral artery, the parietal lobes or thecingulated gyrus), vascular dementia due to hemorrhagic lesions, smallvessel disease (including, e.g. vascular dementia due to lacunar lesionsand Binswanger disease), and mixed dementia.

As used herein, unless otherwise indicated, “blood-brain barrier” or“BBB” are used interchangeably herein, and are used to refer to thepermeable barrier that exists in blood vessels as they travel throughthe brain tissue that severely restricts and closely regulates what isexchanged between the blood and the brain tissue. The blood brainbarrier components include the endothelial cells that form the innermostlining of all blood vessels, the tight junctions between adjacentendothelial cells that are structural correlate of the BBB, the basementmembrane of endothelial cells and the expanded foot process of nearbyastrocytes which cover nearly all of the exposed outer surface of theblood vessel.

As used herein, unless otherwise indicated, “metabolic bone disease” asused herein refers to a varied assortment of bone diseases characterizedby gradual and progressive loss of bone tissue. Metabolic bone diseasesdescribed herein are metabolic bone diseases where there is a conditionof diffusely decreased bone density and/or diminished bone strength.Such diseases are characterized by histological appearance. Exemplarymetabolic bone diseases include, but are not limited to, osteoporosiswhich is characterized by decreased mineral and bone matrix, andosteomalacia which is characterized by decreased mineral but intact bonematrix.

As used herein, unless otherwise indicated, “osteopenic diseases” or“osteopenia” are used interchangeably herein, and refer to conditionswith decreased calcification and/or bone density, and is a descriptiveterm used to refer to all skeletal systems in which decreasedcalcification and/or bone density is observed. Osteopenia also refers toa reduced bone mass due to inadequate osteiod synthesis.

As used herein, unless otherwise indicated, “osteoporosis” refers toconditions in which mineral and/or bone matrix are decreased and/or bonemass is reduced.

As used herein, unless otherwise indicated, “alkyl” is a monovalent,saturated hydrocarbon chain having a specified number of carbon atoms.For example, C₁₋₃alkyl refers to an alkyl group having from 1 to 3carbon atoms. C₁₋₅alkyl refers to an alkyl group having from 1 to 5carbon atoms. Alkyl groups may be straight or branched. In someembodiments, branched alkyl groups may have one, two, or three branches.Exemplary alkyl groups include, but are not limited to, methyl,methylethyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl,isobutyl, and tert-butyl).

As used herein unless otherwise indicated, “alkoxy” substituent is agroup of formula “R—O—”, where R is alkyl as defined above. For example,C₁₋₃alkoxy refers to such an alkoxy substituent containing 1 to 3carbons. Exemplary alkoxy substituents include, but are not limited to,methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexyloxy, isopropoxy,isobutoxy, secbutoxy, tert-butoxy, isopentoxy and neopentoxy. In oneembodiment, C₁₋₃alkoxy refers to methoxy, ethoxy, n-propoxy andisopropoxy.

As used herein, unless otherwise indicated, “C₃₋₆cycloalkyl” is amonovalent radical derived by removal of a hydrogen atom from a 3, 4, 5or 6-membered monocyclic cycloalkane. Exemplary cycloalkyl include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, unless otherwise indicated, “heteroaryl” is a monovalentradical derived by removal of a hydrogen atom from a monocyclic 5 or6-membered heteroaromatic ring, which ring consists of ring-carbon atomsand ring-heteroatoms selected from the group consisting of nitrogen,oxygen and sulphur, and which ring is aromatic. For example, heteroarylis monocyclic heteroaryl consisting of 5 or 6 ring-atoms, 1 to 3 ofwhich are ring-heteroatoms. Exemplary heteroaryls include, but are notlimited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,azepinyl, oxazepinyl, thiazepinyl and diazepinyl. In one embodiment, theheteroaryl refers to pyridinyl, primidinyl and pyrazolyl.

As used herein, unless otherwise indicated, “heterocyclyl” is amonovalent radical derived by removal of a hydrogen atom from a 3, 4, 5or 6-membered saturated monocyclic heterocyclic ring, which ringconsists of ring-carbon atoms and ring-heteroatoms selected from thegroup consisting of nitrogen, oxygen and sulfur. In one embodiment,heterocyclyl is monocyclic saturated heterocyclyl consisting of 3 to 6ring-atoms, and 1 or 2 of which are ring-heteroatoms. Exemplarymonocyclic saturated heterocyclyl substituents include, but are notlimited to, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl,piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino andpiperazinyl. In an embodiment, the heterocyclyl refers to azetidinyl,piperidinyl, pyrrolidinyl and tetrahydro-2H-pyranyl.

As used herein, unless otherwise indicated, “halogen” refers to fluorine(F), chlorine (Cl), bromine (Br), or iodine (I). Halo refers to thehalogen radicals: fluoro (—F), chloro (—Cl), bromo (—Br), or iodo (—I).In one embodiment, halo refers to F.

As used herein, unless otherwise indicated, “haloalkyl” is an alkylgroup substituted by one or more halo substituents, which halosubstituents may be the same or different. For example, C₁₋₃haloalkylrefers to a haloalkyl substituent containing 1 to 3 carbons. Exemplaryhaloalkyl substituents include, but are not limited to,monofluoromethyl, difluoromethyl, trifluoromethyl,1-chloro-2-fluoroethyl, trifluoropropyl, 3-fluoropropyl, and2-fluoroethyl. In one embodiment, C₁₋₃haloalkyl refers totrifluoromethyl, trifluoropropyl, 3-fluoropropyl and 2-fluoroethyl.

As used herein, unless otherwise indicated, when two substituents on aring together with their interconnecting atom(s) combine to form afurther ring, this ring may be spiro fused or orthofused. A spiro-fusedring system consists of two rings which have only one carbon atom incommon. An ortho-fused ring system consists of two rings which have onlytwo atoms and one bond in common.

As used herein, unless otherwise indicated, “optionally substituted”indicates that a group or a ring may be unsubstituted, or the group or aring may be substituted with one or more substituent as defined herein.

As used herein, unless otherwise indicated, “4, 5 or 6 memberedsaturated ring, which ring optionally contains one heteroatom ringmember selected from N or O” reference to 4, 5 or 6 membered saturatedcarbon ring and one carbon atom ring member can be optionally replacedwith one heteroatom selected from N or O, for example, cyclobutanyl,cyclopentanyl, cyclohexanyl, azitidinyl, pyrrolidinyl, piperidinyl,oxetanyl, tetrahydrofuranyl, and tetrahydro-2H-pyranyl.

As used herein, unless otherwise indicated, “substituted” in referenceto a group indicates that one or more hydrogen atom attached to a memberatom (e.g., carbon atom) within the group is replaced with a substituentselected from the group of defined substituents. It should be understoodthat the term “substituted” includes the implicit provision that suchsubstitution be in accordance with the permitted valence of thesubstituted atom and the substituent and that the substitution resultsin a stable compound (i.e. one that does not spontaneously undergotransformation such as by rearrangement, cyclization, or elimination andthat is sufficiently robust to survive isolation from a reactionmixture). When it is stated that a group may contain one or moresubstituent, one or more (as appropriate) member atom within the groupmay be substituted. In addition, a single member atom within the groupmay be substituted with more than one substituent as long as suchsubstitution is in accordance with the permitted valence of the atom.Suitable substituents are defined herein for each substituted oroptionally substituted group.

As used herein, unless otherwise indicated, “treat”, “treating” or“treatment” in reference to a disease means: (1) to ameliorate thedisease or one or more of the biological manifestations of the disease(2) to interfere with (a) one or more points in the biological cascadethat leads to or is responsible for the disease or (b) one or more ofthe biological manifestations of the disease, (3) to alleviate one ormore of the symptoms or effects associated with the disease, (4) to slowthe progression of the disease or one or more of the biologicalmanifestations of the disease, and/or (5) to diminish the likelihood ofseverity of a disease or biological manifestations of the disease. Inone embodiment, “treat” “treating” or “treatment” in reference toAlzheimer's disease means: to slow the progression of congnitivefunction decline.

As used herein, unless otherwise indicated, “prevent”, “preventing” or“prevention” means the prophylactic administration of a drug to diminishthe likelihood of the onset of or to delay the onset of a disease orbiological manifestation thereof.

As used herein, unless otherwise indicated, “subject” means a mammaliansubject (e.g., dog, cat, horse, cow, sheep, goat, monkey, etc.), andparticularly human subjects including both male and female subjects, andincluding neonatal, infant, juvenile, adolescent, adult and geriatricsubjects, and further including various races and ethnicities including,but not limited to, white, black, Asian, American Indian and Hispanic.

As used herein, unless otherwise indicated, “pharmaceutically acceptablesalts” refers to salts that retain the desired biological activity ofthe subject compound and exhibit minimal undesired toxicologicaleffects. These pharmaceutically acceptable salts may be prepared in situduring the final isolation and purification of the compound, or byseparately reacting the purified compound in its free acid or free baseform with a suitable base or acid, respectively.

As used herein, unless otherwise indicated, the term “therapeuticallyeffective amount” means any amount which, as compared to a correspondingsubject who has not received such amount, results in treating orpreventing a disease, but low enough to avoid serious side effects (at areasonable benefit/risk ratio) within the scope of sound medicaljudgment. A therapeutically effective amount of a compound will varywith the particular compound chosen (e.g. consider the potency,efficacy, and half-life of the compound); the route of administrationchosen; the disease being treated; the severity of the disease beingtreated; the age, size, weight, and physical condition of the patientbeing treated; the medical history of the patient to be treated; theduration of the treatment; the nature of concurrent therapy; the desiredtherapeutic effect; and like factors, but can nevertheless be routinelydetermined by the skilled artisan.

B. Compounds

In a first aspect, this invention relates to compounds of Formula (I)and salts (e.g., pharmaceutically acceptable salts) thereof,

wherein

-   -   R¹ is selected from the group consisting of H, C₁₋₃alkyl and        —C(O)—C₁₋₃alkyl; and    -   R² and R³ together with the carbon to which they are attached        form a 4, 5 or 6 membered saturated ring, which ring        -   optionally contains one heteroatom ring member selected from            N or O, and is optionally substituted with one substituent            of -L-K, wherein            -   L is selected from the group consisting of C(O), CH₂,                and S(O)₂, and            -   K is selected from the group consisting of C₁₋₃alkyl,                phenyl, and C₃₋₆cycloalkyl;    -   or R¹ and R² together with the nitrogen and carbon to which they        are attached form a 5 or 6-membered heterocyclic saturated ring,        which ring        -   optionally contains one or two additional heteroatom ring            member independently selected from the group consisting of            N, O, C(O), S, S(O), and S(O)₂, and        -   is optionally substituted with one or more (e.g., one, or            one or two) substituents independently selected from the            group consisting of OH, halo, NR^(1a)R^(1b), COOH, and            —Y—R^(c), wherein            -   Y is absent or is selected from the group consisting of                C(O), S(O)₂, —C(O)—C(O)—, and CH₂, and            -   R^(c) is selected from the group consisting of                -   C₁₋₅alkyl optionally substituted with one or more                    (e.g., one, one or two, or one, two or three)                    substituents independently selected from the group                    consisting of NR^(2a)R^(2b), C₃₋₆ cycloalkyl, and                    —COOH,                -   C₁₋₃haloalkyl,                -   C₁₋₃alkoxyl,                -   NR^(3a)R^(3b),                -   —(CH₂)_(p)—C(O)—O—C₁₋₃alkyl, wherein p is 1, 2, or 3                    and the —(CH₂)_(p)— is optionally substituted by one                    or more (e.g., one or one or two) methyl,                -   —(CH₂)_(q)—C₃₋₆ cycloalkyl, wherein q is 1, 2, or 3,                    wherein the cycloalkyl is optionally substituted                    with NR^(4a)R^(4b), and the —(CH₂)_(q)— is                    optionally substituted by one or more (e.g., one or                    one or two) methyl, and                -   heterocyclyl optionally substituted with one or more                    (e.g., one or one or two) substituents independently                    selected from the group consisting of halo and                    NR^(5a)R^(5b),        -   wherein R^(1a), R^(1b), R^(2a), R^(2b), R^(3a), R^(3b),            R^(4a), R^(4b), R^(5a), and R^(5b) are independently H or            C₁₋₃alkyl; and            R³ is H;            each occurrence of R⁴ is independently H or D;            X is absent or is selected from the group consisting of    -   —O—,    -   —NH—, and    -   —N—(C₁₋₃ alkyl)-,        n is 1 or 2;        or X is —O—CH₂— bicyclo[1.1.1]pentanyl-CH₂—O— and n is 0; and        A is unsubstituted thiophenyl, or        A is

wherein

-   -   R⁵ and R⁹ are independently H or halo,    -   Z′ is N or CR⁶,    -   Z is N or CR⁸,        -   wherein R⁶ and R⁸ are independently selected from the group            consisting of H, CN, halo, C₁₋₃alkyl, C₁₋₃haloalkyl,            —S(O)₂—C₁₋₃alkyl and —S(O)—C₁₋₃alkyl, and    -   V is N or CR⁷, wherein R⁷ is selected from the group consisting        of H, halo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, and —S(O)₂—C₁₋₃alkyl,        or R⁷ is -Q-(CH₂)_(m)—W, wherein        -   Q is O, N, or CH₂,        -   m is 0 or 1, and        -   W is selected from the group consisting of C₃₋₆ cycloalkyl,            heterocyclyl, 5 or 6 membered heteroaryl and phenyl, wherein            said cycloalkyl, heterocyclyl, heteroaryl or phenyl is            optionally substituted with one or more (e.g., one, or one            or two) substituents independently selected from the group            consisting of C₁₋₃haloalkyl, CN, halo and C₁₋₅ alkyl;    -   or when Z or Z′ is CR⁶ and V is CR⁷, R⁶ and R⁷ together may form        a 4,7-dioxaspiro[2.6]nonane;        with the proviso that the compound of Formula (I) is not

-   2-fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile,

-   7-(2,3-difluorophenethyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one,

-   7-((2,3-difluorobenzyl)amino)-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione,

-   7-((3,4-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one    2,2-dioxide,

-   7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one-2-oxide,    or

-   7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one-2,2-dioxide.

This invention provides, in a further aspect, compounds of Formula (I-1)and pharmaceutically acceptable salts thereof:

wherein

-   -   R¹ is selected from the group consisting of H, C₁₋₃alkyl and        —C(O)—C₁₋₃alkyl; and    -   R² and R³ together with the carbon to which they are attached        form a 4, 5 or 6 membered saturated ring, which ring        -   optionally contains one heteroatom ring member selected from            N or O, and        -   is optionally substituted with one substituent of -L-K,            wherein            -   L is selected from the group consisting of C(O), CH₂,                and S(O)₂, and            -   K is selected from the group consisting of C₁₋₃alkyl,                phenyl, and C₃₋₆cycloalkyl;    -   or R¹ and R² together with the nitrogen and carbon to which they        are attached form a 5 or 6-membered heterocyclic saturated ring,        which ring        -   optionally contains one or two additional heteroatom ring            member independently selected from the group consisting of            N, O, C(O), S, S(O), and S(O)₂, and        -   is optionally substituted with one or more (e.g., one, or            one or two) substituents independently selected from the            group consisting of OH, halo, NR^(1a)R^(1b), COOH, and            —Y—R^(c), wherein            -   Y is absent or is selected from the group consisting of                C(O), S(O)₂, —C(O)—C(O)—, and CH₂, and            -   R^(c) is selected from the group consisting of                -   C₁₋₅alkyl optionally substituted with one or more                    (e.g., one, one or two, or one, two or three)                    substituents independently selected from the group                    consisting of NR^(2a)R^(2b), C₃₋₆ cycloalkyl, and                    —COOH,                -   C₁₋₃haloalkyl,                -   C₁₋₃alkoxyl,                -   NR^(3a)R^(3b),                -   —(CH₂)_(p)—C(O)—O—C₁₋₃alkyl, wherein p is 1, 2, or 3                    and the —(CH₂)_(p)— is optionally substituted by one                    or more (e.g., one or one or two) methyl,                -   —(CH₂)_(q)—C₃₋₆ cycloalkyl wherein q is 1, 2, or 3,                    wherein the cycloalkyl is optionally substituted                    with NR^(4a)R^(4b), and the —(CH₂)_(q)— is                    optionally substituted by one or more (e.g., one or                    one or two) methyl, and                -   heterocyclyl optionally substituted with one or more                    (e.g., one or one or two) substituents independently                    selected from the group consisting of halo and                    NR^(5a)R^(5b),        -   wherein R^(1a), R^(1b), R^(2a), R^(2b), R^(3a), R^(3b),            R^(4a), R^(4b), R^(5a), and R^(5b) are independently H or            C₁₋₃alkyl; and    -   R³ is H;    -   each occurrence of R⁴ is independently H or D;    -   X is absent or is selected from the group consisting of        -   —O—,        -   —NH—, and        -   —N(C₁₋₃ alkyl)-,    -   n is 1 or 2;    -   or X is —O—CH₂— bicyclo[1.1.1]pentanyl-CH₂—O— and n is 0; and    -   A is unsubstituted thiophenyl, or    -   A is

wherein

-   -   R⁵ and R⁹ are independently H or halo,    -   Z′ is N or CR⁶,    -   Z is N or CR⁸,        -   wherein R⁶ and R⁸ are independently selected from the group            consisting of H, CN, halo, C₁₋₃alkyl, C₁₋₃haloalkyl,            —S(O)₂—C₁₋₃alkyl and —S(O)—C₁₋₃alkyl, and    -   V is N or CR⁷, wherein R⁷ is selected from the group consisting        of H, halo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, and —S(O)₂—C₁₋₃alkyl,        or R⁷ is -Q-(CH₂)_(m)—W,        -   wherein            -   Q is O, N, or CH₂,            -   m is 0 or 1, and            -   W is selected from the group consisting of                C₃₋₆cycloalkyl, heterocyclyl, 5 or 6 membered heteroaryl                and phenyl, wherein said cycloalkyl, heterocyclyl,                heteroaryl or phenyl is optionally substituted with one                or more (e.g., one, or one or two) substituents                independently selected from the group consisting of                C₁₋₃haloalkyl, CN, halo and C₁₋₅ alkyl;    -   or when Z or Z′ is CR⁶ and V is CR⁷, R⁶ and R⁷ together may form        a 4,7-dioxaspiro[2.6]nonane;

with the proviso that the compound of Formula (I-1) is not

-   2-fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile,-   7-(2,3-difluorophenethyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one,-   7-((2,3-difluorobenzyl)amino)-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione,-   7-((3,4-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one    2,2-dioxide,-   7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one-2-oxide,-   7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one-2,2-dioxide,-   7-(2,3-difluorophenethyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one,-   4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-spiro[cyclobutane-1,2′-imidazo[1,2-c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile,-   4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-spiro[cyclopentane-1,2′-imidazo[1,2-c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile,    or-   4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-spiro[cyclohexane-1,2′-imidazo[1,2-c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile.

In one embodiment, this invention relates to compounds of Formula (I-2)and pharmaceutically acceptable salts thereof:

wherein

-   -   R¹ is selected from the group consisting of H, C₁₋₃alkyl and        —C(O)—C₁₋₃alkyl; and    -   R² and R³ together with the carbon to which they are attached        form a 4, 5 or 6 membered saturated ring, which ring        -   optionally contains one heteroatom ring member selected from            N or O, and        -   is optionally substituted with one substituent of -L-K,            wherein            -   L is selected from the group consisting of C(O), CH₂,                and S(O)₂, and            -   K is selected from the group consisting of C₁₋₃alkyl,                phenyl, and C₃₋₆cycloalkyl;    -   or R¹ and R² together with the nitrogen and carbon to which they        are attached form a 5 or 6-membered heterocyclic saturated ring,        which ring        -   optionally contains one or two additional heteroatom ring            member independently selected from the group consisting of            N, O, C(O), S, S(O), and S(O)₂, and        -   is optionally substituted with one or more (e.g., one, or            one or two) substituents independently selected from the            group consisting of OH, halo, NR^(1a)R^(1b), COOH, and            —Y—R^(c), wherein            -   Y is absent or is selected from the group consisting of                C(O), S(O)₂, —C(O)—C(O)—, and CH₂, and            -   R^(c) is selected from the group consisting of                -   C₁₋₅alkyl optionally substituted with one or more                    (e.g., one, one or two, or one, two or three)                    substituents independently selected from the group                    consisting of NR^(2a)R^(2b), C₃₋₆ cycloalkyl, and                    —COOH,                -   C₁₋₃haloalkyl,                -   C₁₋₃alkoxyl,                -   NR^(3a)R^(3b),                -   —(CH₂)_(p)—C(O)—O—C₁₋₃alkyl, wherein p is 1, 2, or 3                    and the —(CH₂)_(p)— is optionally substituted by one                    or more (e.g., one or one or two) methyl,                -   —(CH₂)_(q)—C₃₋₆ cycloalkyl, wherein q is 1, 2, or 3,                    wherein the cycloalkyl is optionally substituted                    with NR^(4a)R^(4b) and the —(CH₂)_(q)— is optionally                    substituted by one or more (e.g., one or one or two)                    methyl, and                -   heterocyclyl optionally substituted with one or more                    (e.g., one or one or two) substituents independently                    selected from the group consisting of halo and                    NR^(5a)R^(5b),        -   wherein R^(1a), R^(1b), R^(2a), R^(2b), R^(3a), R^(3b),            R^(4a), R^(4b), R^(5a), and R^(5b) are independently H or            C₁₋₃alkyl; and    -   R³ is H;    -   each occurrence of R⁴ is independently H or D;    -   X is absent or is selected from the group consisting of        -   —O—,        -   —NH—, and        -   —N(C₁₋₃ alkyl)-,    -   n is 1 or 2;    -   or X is —O—CH₂— bicyclo[1.1.1]pentanyl-CH₂—O— and n is 0; and    -   A is unsubstituted thiophenyl, or    -   A is

wherein

-   -   R⁵ and R⁹ are independently H or halo,    -   Z′ is N or CR⁶,    -   Z is N or CR⁸,        -   wherein R⁶ and R⁸ are independently selected from the group            consisting of H, CN, halo, C₁₋₃alkyl, C₁₋₃haloalkyl,            —S(O)₂—C₁₋₃alkyl and —S(O)—C₁₋₃alkyl, and    -   V is N or CR⁷, wherein R⁷ is selected from the group consisting        of H, halo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, and —S(O)₂—C₁₋₃alkyl,        or R⁷ is -Q-(CH₂)_(m)—W, wherein        -   Q is O, N, or CH₂,        -   m is 0 or 1, and        -   W is selected from the group consisting of C₃₋₆cycloalkyl,            heterocyclyl, 5 or 6 membered heteroaryl and phenyl, wherein            said cycloalkyl, heterocyclyl, heteroaryl or phenyl is            optionally substituted with one or more (e.g., one, or one            or two) substituents independently selected from the group            consisting of C₁₋₃haloalkyl, CN, halo and C₁₋₅ alkyl;    -   or when Z or Z′ is CR⁶ and V is CR⁷, R⁶ and R⁷ together may form        a 4,7-dioxaspiro[2.6]nonane;

with the proviso that the compound of Formula (I-2) is not

-   2-fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile,-   7-(2,3-difluorophenethyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one,-   7-((2,3-difluorobenzyl)amino)-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione,-   7-((3,4-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one    2,2-dioxide,-   7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one-2-oxide,-   7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one-2,2-dioxide,-   7-(2,3-difluorophenethyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one,-   4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-spiro[cyclobutane-1,2′-imidazo[1,2-c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile,-   4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-spiro[cyclopentane-1,2′-imidazo[1,2-c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile,    or-   4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-spiro[cyclohexane-1,2′-imidazo[1,2-c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile,

and the compound of Formula (I-2) is not

-   -   wherein    -   R^(I) is H or F;    -   R^(II) is selected from the group consisting of H, halo, CN, and        CF₃;    -   R^(III) is selected from the group consisting of H, F, CN, CF₃,        CH₃, and —O—Y, wherein    -   Y is a phenyl, pyridinyl or pyrimidinyl, wherein the phenyl,        pyridinyl or pyrimidinyl is substituted with one or more        substituents independently selected from the group consisting of        halo, CF₃ and CN; and    -   R^(IV) is selected from the group consisting of CN, H, F and        CH₃.

This invention provides, in a further aspect, compounds of Formula (I-3)and pharmaceutically acceptable salts thereof:

wherein

-   -   R¹ is selected from the group consisting of H, C₁₋₃alkyl and        —C(O)—C₁₋₃alkyl; and    -   R² and R³ together with the carbon to which they are attached        form a 4, 5 or 6 membered saturated ring, which ring        -   optionally contains one heteroatom ring member selected from            N or O, and        -   is optionally substituted with one substituent of -L-K,            wherein            -   L is selected from the group consisting of C(O), CH₂,                and S(O)₂, and            -   K is selected from the group consisting of C₁₋₃alkyl,                phenyl, and C₃₋₆cycloalkyl;    -   or R¹ and R² together with the nitrogen and carbon to which they        are attached form a 5-membered heterocyclic saturated ring,        which ring        -   optionally contains one or two additional heteroatom ring            member independently selected from the group consisting of            N, O, C(O), S, S(O), and S(O)₂, and        -   is optionally substituted with one or more (e.g., one, or            one or two) substituents independently selected from the            group consisting of OH, halo, NR^(1a)R^(1b), COOH, and            —Y—R^(c), wherein            -   Y is absent or is selected from the group consisting of                C(O), S(O)₂, —C(O)—C(O)—, and CH₂, and            -   R^(c) is selected from the group consisting of                -    C₁₋₅alkyl optionally substituted with one or more                    (e.g., one, one or two, or one, two or three)                    substituents independently selected from the group                    consisting of NR^(2a)R^(2b), C₃₋₆ cycloalkyl, and                    —COOH,                -    C₁₋₃haloalkyl,                -    C₁₋₃alkoxyl,                -    NR^(3a)R^(3b),                -    —(CH₂)_(p)—C(O)—O—C₁₋₃alkyl, wherein p is 1, 2, or                    3 and the —(CH₂)_(p)— is optionally substituted by                    one or more (e.g., one or one or two) methyl,                -    —(CH₂)_(q)—C₃₋₆ cycloalkyl, wherein q is 1, 2, or 3                    wherein the cycloalkyl is optionally substituted                    with NR^(4a)R^(4b) and the —(CH₂)_(q)— is optionally                    substituted by one or more (e.g., one or one or two)                    methyl, and                -    heterocyclyl optionally substituted with one or                    more (e.g., one or one or two) substituents                    independently selected from the group consisting of                    halo and NR^(5a)R^(5b),        -   wherein R^(1a), R^(1b), R^(2a), R^(2b), R^(3a), R^(3b),            R^(4a), R^(4b), R^(5a), and R^(5b) are independently H or            C₁₋₃alkyl; and    -   R³ is H;    -   each occurrence of R⁴ is independently H or D;    -   X is absent or is selected from the group consisting of        -   —O—,        -   —NH—, and        -   —N(C₁₋₃ alkyl)-,    -   n is 1 or 2;    -   or X is —O—CH₂— bicyclo[1.1.1]pentanyl-CH₂—O— and n is 0; and    -   A is unsubstituted thiophenyl, or    -   A is

wherein

-   -   R⁵ and R⁹ are independently H or halo,    -   Z′ is N or CR⁶,    -   Z is N or CR⁸,        -   wherein R⁶ and R⁸ are independently selected from the group            consisting of H, CN, halo, C₁₋₃alkyl, C₁₋₃haloalkyl,            —S(O)₂—C₁₋₃alkyl and —S(O)—C₁₋₃alkyl, and    -   V is N or CR⁷, wherein R⁷ is selected from the group consisting        of H, halo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, and —S(O)₂—C₁₋₃alkyl,        or R⁷ is -Q-(CH₂)_(m)—W, wherein        -   Q is O, N, or CH₂,        -   m is 0 or 1, and        -   W is selected from the group consisting of C₃₋₆cycloalkyl,            heterocyclyl, 5 or 6 membered heteroaryl and phenyl, wherein            said cycloalkyl, heterocyclyl, heteroaryl or phenyl is            optionally substituted with one or more (e.g., one, or one            or two) substituents independently selected from the group            consisting of C₁₋₃haloalkyl, CN, halo and C₁₋₅ alkyl;    -   or when Z or Z′ is CR⁶ and V is CR⁷, R⁶ and R⁷ together may form        a 4,7-dioxaspiro[2.6]nonane,

with the proviso that the compound of Formula (I-2) is not

-   4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-spiro[cyclobutane-1,2′-imidazo[1,2-c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile,-   4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-spiro[cyclopentane-1,2′-imidazo[1,2-c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile,    or-   4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-spiro[cyclohexane-1,2′-imidazo[1,2-c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile.

This invention provides, in a further aspect, compounds of Formula (I-4)and pharmaceutically acceptable salts thereof:

wherein

-   -   R¹ is selected from the group consisting of H, C₁₋₃alkyl and        —C(O)—C₁₋₃alkyl; and    -   R² and R³ together with the carbon to which they are attached        form a 4, 5 or 6 membered saturated ring, which ring        -   optionally contains one heteroatom ring member selected from            N or O, and        -   is optionally substituted with one substituent of -L-K,            wherein            -   L is selected from the group consisting of C(O), CH₂,                and S(O)₂, and            -   K is selected from the group consisting of C₁₋₃alkyl,                phenyl, and            -   C₃₋₆cycloalkyl;    -   or R¹ and R² together with the nitrogen and carbon to which they        are attached form a 6-membered heterocyclic saturated ring,        which ring        -   optionally contains one or two additional heteroatom ring            member independently selected from the group consisting of            N, O, C(O), S, S(O), and S(O)₂, and        -   is optionally substituted with one or more (e.g., one, or            one or two) substituents independently selected from the            group consisting of OH, halo, NR^(1a)R^(1b), COOH, and            —Y—R^(c), wherein            -   Y is absent or is selected from the group consisting of                C(O), S(O)₂, —C(O)—C(O)—, and CH₂, and            -   R^(c) is selected from the group consisting of                -   C₁₋₅alkyl optionally substituted with one or more                    (e.g., one, one or two, or one, two or three)                    substituents independently selected from the group                    consisting of NR^(2a)R^(2b), C₃₋₆ cycloalkyl, and                    —COOH,                -   C₁₋₃haloalkyl,                -   C₁₋₃alkoxyl,                -   NR^(3a)R^(3b),                -   —(CH₂)_(p)—C(O)—O—C₁₋₃alkyl, wherein p is 1, 2, or 3                    and the —(CH₂)_(p)— is optionally substituted by one                    or more (e.g., one or one or two) methyl,                -   —(CH₂)_(q)—C₃₋₆ cycloalkyl, wherein q is 1, 2, or 3                    wherein the cycloalkyl is optionally substituted                    with NR^(4a)R^(4b), and the —(CH₂)_(q)— is                    optionally substituted by one or more (e.g., one or                    one or two) methyl, and                -   heterocyclyl optionally substituted with one or more                    (e.g., one or one or two) substituents independently                    selected from the group consisting of halo and                    NR^(5a)R^(5b),        -   wherein R^(1a), R^(1b), R^(2a), R^(2b), R^(3a), R^(3b),            R^(4a), R^(4b), R^(5a), and R^(5b) are independently H or            C₁₋₃alkyl; and    -   R³ is H;    -   each occurrence of R⁴ is independently H or D;    -   X is absent or is selected from the group consisting of        -   —O—,        -   —NH—, and        -   —N(C₁₋₃ alkyl)-,    -   n is 1 or 2;    -   or X is —O—CH₂— bicyclo[1.1.1]pentanyl-CH₂—O— and n is 0; and    -   A is unsubstituted thiophenyl, or    -   A is

wherein

-   -   R⁵ and R⁹ are independently H or halo,    -   Z′ is N or CR⁶,    -   Z is N or CR⁸,        -   wherein R⁶ and R⁸ are independently selected from the group            consisting of H, CN, halo, C₁₋₃alkyl, C₁₋₃haloalkyl,            —S(O)₂—C₁₋₃alkyl and —S(O)—C₁₋₃alkyl, and    -   V is N or CR⁷, wherein R⁷ is selected from the group consisting        of H, halo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, and —S(O)₂—C₁₋₃alkyl,        or R⁷ is -Q-(CH₂)_(m)—W, wherein        -   Q is O, N, or CH₂,        -   m is 0 or 1, and        -   W is selected from the group consisting of C₃₋₆cycloalkyl,            heterocyclyl, 5 or 6 membered heteroaryl and phenyl, wherein            said cycloalkyl, heterocyclyl, heteroaryl or phenyl is            optionally substituted with one or more (e.g., one, or one            or two) substituents independently selected from the group            consisting of C₁₋₃haloalkyl, CN, halo and C₁₋₅ alkyl;    -   or when Z or Z′ is CR⁶ and V is CR⁷, R⁶ and R⁷ together may form        a 4,7-dioxaspiro[2.6]nonane;

with the proviso that the compound of Formula (I-4) is not

-   2-fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile,-   7-(2,3-difluorophenethyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one,-   7-((2,3-difluorobenzyl)amino)-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione,-   7-((3,4-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one    2,2-dioxide,-   7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one-2-oxide,-   7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one-2,2-dioxide,-   7-(2,3-Difluorophenethyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one,-   4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-spiro[cyclobutane-1,2′-imidazo[1,2-c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile,-   4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-spiro[cyclopentane-1,2′-imidazo[1,2-c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile,    or-   4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-spiro[cyclohexane-1,2′-imidazo[1,2-c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile.

In one embodiment, this invention relates to compounds of Formula (I-5)and pharmaceutically acceptable salts thereof:

wherein

-   -   R¹ is selected from the group consisting of H, C₁₋₃alkyl and        —C(O)—C₁₋₃alkyl; and    -   R² and R³ together with the carbon to which they are attached        form a 4, 5 or 6 membered saturated ring, which ring        -   optionally contains one heteroatom ring member selected from            N or O, and        -   is optionally substituted with one substituent of -L-K,            wherein            -   L is selected from the group consisting of C(O), CH₂,                and S(O)₂, and            -   K is selected from the group consisting of C₁₋₃alkyl,                phenyl, and C₃₋₆cycloalkyl;    -   or R¹ and R² together with the nitrogen and carbon to which they        are attached form a 6-membered heterocyclic saturated ring,        which ring        -   optionally contains one or two additional heteroatom ring            member independently selected from the group consisting of            N, O, C(O), S, S(O), and S(O)₂, and        -   is optionally substituted with one or more (e.g., one, or            one or two) substituents independently selected from the            group consisting of OH, halo, NR^(1a)R^(1b), COOH, and            —Y—R^(c), wherein            -   Y is absent or is selected from the group consisting of                C(O), S(O)₂, —C(O)—C(O)—, and CH₂, and            -   R^(c) is selected from the group consisting of                -   C₁₋₅alkyl optionally substituted with one or more                    (e.g., one, one or two, or one, two or three)                    substituents independently selected from the group                    consisting of NR^(2a)R^(2b), C₃₋₆ cycloalkyl, and                    —COOH,                -   C₁₋₃haloalkyl,                -   C₁₋₃alkoxyl,                -   NR^(3a)R^(3b),                -   —(CH₂)_(p)—C(O)—O—C₁₋₃alkyl, wherein p is 1, 2, or 3                    and the —(CH₂)_(p)— is optionally substituted by one                    or more (e.g., one or one or two) methyl,                -   —(CH₂)_(q)—C₃₋₆ cycloalkyl, wherein q is 1, 2, or 3                    wherein the cycloalkyl is optionally substituted                    with NR^(4a)R^(4b) and the —(CH₂)_(q)— is optionally                    substituted by one or more (e.g., one or one or two)                    methyl, and                -   heterocyclyl optionally substituted with one or more                    (e.g., one or one or two) substituents independently                    selected from the group consisting of halo and                    NR^(5a)R^(5b),        -   wherein R^(1a), R^(1b), R^(2a), R^(2b), R^(3a), R^(3b),            R^(4a), R^(4b), R^(5a), and R^(5b) are independently H or            C₁₋₃alkyl; and    -   R³ is H;    -   each occurrence of R⁴ is independently H or D;    -   X is absent or is selected from the group consisting of        -   —O—,        -   —NH—, and        -   —N(C₁₋₃ alkyl)-,    -   n is 1 or 2;    -   or X is —O—CH₂— bicyclo[1.1.1]pentanyl-CH₂—O— and n is 0; and    -   A is unsubstituted thiophenyl, or    -   A is

wherein

-   -   R⁵ and R⁹ are independently H or halo,    -   Z′ is N or CR⁶,    -   Z is N or CR⁸,        -   wherein R⁶ and R⁸ are independently selected from the group            consisting of H, CN, halo, C₁₋₃alkyl, C₁₋₃haloalkyl,            —S(O)₂—C₁₋₃alkyl and —S(O)—C₁₋₃alkyl, and    -   V is N or CR⁷, wherein R⁷ is selected from the group consisting        of H, halo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, and —S(O)₂—C₁₋₃alkyl,        or R⁷ is -Q-(CH₂)_(m)—W, wherein        -   Q is O, N, or CH₂,        -   m is 0 or 1, and        -   W is selected from the group consisting of C₃₋₆cycloalkyl,            heterocyclyl, 5 or 6 membered heteroaryl and phenyl, wherein            said cycloalkyl, heterocyclyl, heteroaryl or phenyl is            optionally substituted with one or more (e.g., one, or one            or two) substituents independently selected from the group            consisting of C₁₋₃haloalkyl, CN, halo and C₁₋₅ alkyl;    -   or when Z or Z′ is CR⁶ and V is CR⁷, R⁶ and R⁷ together may form        a 4,7-dioxaspiro[2.6]nonane;

with the proviso that the compound of Formula (I-5) is not

-   2-fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile,-   7-(2,3-difluorophenethyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one,-   7-((2,3-difluorobenzyl)amino)-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione,-   7-((3,4-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one    2,2-dioxide,-   7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one-2-oxide,-   7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one-2,2-dioxide,-   7-(2,3-Difluorophenethyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one,-   4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-spiro[cyclobutane-1,2′-imidazo[1,2-c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile,-   4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-spiro[cyclopentane-1,2′-imidazo[1,2-c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile,    or-   4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-spiro[cyclohexane-1,2′-imidazo[1,2-c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile,

and the compound of Formula (I-5) is not

-   -   wherein    -   R^(I) is H or F;    -   R^(II) is selected from the group consisting of H, halo, CN, and        CF₃;    -   R^(III) is selected from the group consisting of H, F, CN, CF₃,        CH₃, and —O—Y, wherein    -   Y is a phenyl, pyridinyl or pyrimidinyl, wherein the phenyl,        pyridinyl or pyrimidinyl is substituted with one or more        substituents independently selected from the group consisting of        halo, CF₃ and CN; and    -   R^(IV) is selected from the group consisting of CN, H, F and        CH₃.

In a further embodiment, the present invention provides compounds ofFormula (II-1) and pharmaceutically acceptable salts thereof

wherein

-   -   R¹ and R² together with the nitrogen and carbon to which they        are attached form a 5 or 6-membered heterocyclic saturated ring,        which ring        -   optionally contains one or two additional heteroatom ring            member independently selected from the group consisting of            N, O, C(O), S, S(O), and S(O)₂, and        -   is optionally substituted with one or more (e.g., one, or            one or two) substituents independently selected from the            group consisting of OH, halo, NR^(1a)R^(1b), COOH, and            —Y—R^(c), wherein            -   Y is absent or is selected from the group consisting of                C(O), S(O)₂, —C(O)—C(O)—, and CH₂, and            -   R^(c) is selected from the group consisting of                -   C₁₋₅alkyl optionally substituted with one or more                    (e.g., one, one or two, or one, two or three)                    substituents independently selected from the group                    consisting of NR^(2a)R^(2b), C₃₋₆ cycloalkyl, and                    —COOH,                -   C₁₋₃haloalkyl,                -   C₁₋₃alkoxyl,                -   NR^(3a)R^(3b),                -   —(CH₂)_(p)—C(O)—O—C₁₋₃alkyl, wherein p is 1, 2, or 3                    and the —(CH₂)_(p)— is optionally substituted by one                    or more (e.g., one or one or two) methyl,                -   —(CH₂)_(q)—C₃₋₆ cycloalkyl, wherein q is 1, 2, or 3,                    wherein the cycloalkyl is optionally substituted                    with NR^(4a)R^(4b), and the —(CH₂)_(q)— is                    optionally substituted by one or more (e.g., one or                    one or two) methyl, and                -   heterocyclyl optionally substituted with one or more                    (e.g., one or one or two) substituents independently                    selected from the group consisting of halo and                    NR^(5a)R^(5b),        -   wherein R^(1a), R^(1b), R^(2a), R^(2b), R^(3a), R^(3b),            R^(4a), R^(4b), R^(5a), and R^(5b) are independently H or            C₁₋₃alkyl; and    -   R³ is H;    -   each occurrence of R⁴ is independently H or D;    -   X is absent or is selected from the group consisting of        -   —O—,        -   —NH—, and        -   —N(C₁₋₃ alkyl)-,    -   n is 0, 1 or 2;    -   or X is —O—CH₂— bicyclo[1.1.1]pentanyl-CH₂—O— and n is 0; and    -   A is unsubstituted thiophenyl, or    -   A is

wherein

-   -   R⁵ and R⁹ are independently H or halo,    -   Z′ is N or CR⁶,    -   Z is N or CR⁸,    -   wherein R⁶ and R⁸ are independently selected from the group        consisting of H, CN, halo, C₁₋₃alkyl, C₁₋₃haloalkyl,        —S(O)₂—C₁₋₃alkyl and —S(O)—C₁₋₃alkyl, and    -   V is N or CR⁷, wherein R⁷ is selected from the group consisting        of H, halo, CN, C₁₋₃alkyl, C₁₋₃ alkyl, C₁₋₃haloalkyl, and        —S(O)₂—C₁₋₃alkyl, or R⁷ is -Q-(CH₂)_(m)—W, wherein        -   Q is O, N, or CH₂,        -   m is 0 or 1, and        -   W is selected from the group consisting of C₃₋₆ cycloalkyl,            heterocyclyl, 5 or 6 membered heteroaryl and phenyl, wherein            said cycloalkyl, heterocyclyl, heteroaryl or phenyl is            optionally substituted with one or more (e.g., one, or one            or two) substituents independently selected from the group            consisting of C₁₋₃haloalkyl, CN, halo and C₁₋₅ alkyl;    -   or when Z or Z′ is CR⁶ and V is CR⁷, R⁶ and R⁷ together may form        a 4,7-dioxaspiro[2.6]nonane,

with the proviso that the compound of Formula (II-1) is not

-   2-fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile,-   7-(2,3-difluorophenethyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one,-   7-((2,3-difluorobenzyl)amino)-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione,-   7-((3,4-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one    2,2-dioxide,-   7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one-2-oxide,-   7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one-2,2-dioxide,    and-   7-(2,3-Difluorophenethyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one.

In a further embodiment, the present invention provides compounds ofFormula (II-2) and pharmaceutically acceptable salts thereof

wherein

-   -   R¹ and R² together with the nitrogen and carbon to which they        are attached form a 5 or 6-membered heterocyclic saturated ring,        which ring        -   optionally contains one or two additional heteroatom ring            member independently selected from the group consisting of            N, O, C(O), S, S(O), and S(O)₂, and        -   is optionally substituted with one or more (e.g., one, or            one or two) substituents independently selected from the            group consisting of OH, halo, NR^(1a)R^(1b), COOH, and            —Y—R^(c), wherein            -   Y is absent or is selected from the group consisting of                C(O), S(O)₂, —C(O)—C(O)—, and CH₂, and            -   R^(c) is selected from the group consisting of                -   C₁₋₅alkyl optionally substituted with one or more                    (e.g., one, one or two, or one, two or three)                    substituents independently selected from the group                    consisting of NR^(2a)R^(2b), C₃₋₆ cycloalkyl, and                    —COOH,                -   C₁₋₃haloalkyl,                -   C₁₋₃alkoxyl,                -   NR^(3a)R^(3b),                -   —(CH₂)_(p)—C(O)—O—C₁₋₃alkyl, wherein p is 1, 2, or 3                    and the —(CH₂)_(p)— is optionally substituted by one                    or more (e.g., one or one or two) methyl,                -   —(CH₂)_(q)—C₃₋₆ cycloalkyl, wherein q is 1, 2, or 3,                    wherein the cycloalkyl is optionally substituted                    with NR^(4a)R^(4b) and the —(CH₂)_(q)— is optionally                    substituted by one or more (e.g., one or one or two)                    methyl, and                -   heterocyclyl optionally substituted with one or more                    (e.g., one or one or two) substituents independently                    selected from the group consisting of halo and                    NR^(5a)R^(5b),        -   wherein R^(1a), R^(1b), R^(2a), R^(2b), R^(3a), R^(3b),            R^(4a), R^(4b), R^(5a), and R^(5b) are independently H or            C₁₋₃alkyl; and    -   R³ is H;    -   each occurrence of R⁴ is independently H or D;    -   X is absent or is selected from the group consisting of        -   —O—,        -   —NH—, and        -   —N(C₁₋₃ alkyl)-,    -   n is 0, 1 or 2;    -   or X is —O—CH₂— bicyclo[1.1.1]pentanyl-CH₂—O—, and n is 0; and    -   A is unsubstituted thiophenyl, or    -   A is

wherein

-   -   R⁵ and R⁹ are independently H or halo,    -   Z′ is N or CR⁶,    -   Z is N or CR⁸,    -   wherein R⁶ and R⁸ are independently selected from the group        consisting of H, CN, halo, C₁₋₃alkyl, C₁₋₃haloalkyl,        —S(O)₂—C₁₋₃alkyl and —S(O)—C₁₋₃ alkyl, and    -   V is N or CR⁷, wherein R⁷ is selected from the group consisting        of H, halo, CN, C₁₋₃alkyl, C₁₋₃ alkyl, C₁₋₃haloalkyl, and        —S(O)₂—C₁₋₃alkyl, or R⁷ is -Q-(CH₂)_(m)—W, wherein        -   Q is O, N, or CH₂,        -   m is 0 or 1, and        -   W is selected from the group consisting of C₃₋₆ cycloalkyl,            heterocyclyl, 5 or 6 membered heteroaryl and phenyl, wherein            said cycloalkyl, heterocyclyl, heteroaryl or phenyl is            optionally substituted with one or more (e.g., one, or one            or two) substituents independently selected from the group            consisting of C₁₋₃haloalkyl, CN, halo and C₁₋₅ alkyl;    -   or when Z or Z′ is CR⁶ and V is CR⁷, R⁶ and R⁷ together may form        a 4,7-dioxaspiro[2.6]nonane,

with the proviso that the compound of Formula (II-2) is not

-   2-fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile,-   7-(2,3-difluorophenethyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one,-   7-((2,3-difluorobenzyl)amino)-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione,-   7-((3,4-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one    2,2-dioxide,-   7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one-2-oxide,-   7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one-2,2-dioxide,    or-   7-(2,3-Difluorophenethyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one,

and the compound of Formula (II-2) is not

-   -   wherein    -   R^(I) is H or F;    -   R^(II) is selected from the group consisting of H, halo, CN, and        CF₃;    -   R^(III) is selected from the group consisting of H, F, CN, CF₃,        CH₃, and —O—Y, wherein    -   Y is a phenyl, pyridinyl or pyrimidinyl, wherein the phenyl,        pyridinyl or pyrimidinyl is substituted with one or more        substituents independently selected from the group consisting of        halo, CF₃ and CN; and    -   R^(IV) is selected from the group consisting of CN, H, F and        CH₃.

In a further embodiment, the present invention provides compounds ofFormula (II-3) and pharmaceutically acceptable salts thereof

wherein

-   -   R¹ and R² together with the nitrogen and carbon to which they        are attached form a 5-membered heterocyclic saturated ring,        which ring        -   optionally contains one or two additional heteroatom ring            member independently selected from the group consisting of            N, O, C(O), S, S(O), and S(O)₂, and        -   is optionally substituted with one or more (e.g., one, or            one or two) substituents independently selected from the            group consisting of OH, halo, NR^(1a)R^(1b), COOH, and            —Y—R^(c), wherein            -   Y is absent or is selected from the group consisting of                C(O), S(O)₂, —C(O)—C(O)—, and CH₂, and            -   R^(c) is selected from the group consisting of                -   C₁₋₅alkyl optionally substituted with one or more                    (e.g., one, one or two, or one, two or three)                    substituents independently selected from the group                    consisting of NR^(2a)R^(2b), C₃₋₆ cycloalkyl, and                    —COOH,                -   C₁₋₃haloalkyl,                -   C₁₋₃alkoxyl,                -   NR^(3a)R^(3b),                -   —(CH₂)_(p)—C(O)—O—C₁₋₃alkyl, wherein p is 1, 2, or 3                    and the —(CH₂)_(p)— is optionally substituted by one                    or more (e.g., one or one or two) methyl,                -   —(CH₂)_(q)—C₃₋₆ cycloalkyl, wherein q is 1, 2, or 3,                    wherein the cycloalkyl is optionally substituted                    with NR^(4a)R^(4b) and the —(CH₂)_(q)— is optionally                    substituted by one or more (e.g., one or one or two)                    methyl, and                -   heterocyclyl optionally substituted with one or more                    (e.g., one or one or two) substituents independently                    selected from the group consisting of halo and                    NR^(5a)R^(5b),        -   wherein R^(1a), R^(1b), R^(2a), R^(2b), R^(3a), R^(3b),            R^(4a), R^(4b), R^(5a), and R^(5b) are independently H or            C₁₋₃alkyl; and    -   R³ is H;    -   each occurrence of R⁴ is independently H or D;    -   X is absent or is selected from the group consisting of        -   —O—,        -   —NH—, and        -   —N(C₁₋₃ alkyl)-,    -   n is 0, 1 or 2;    -   or X is —O—CH₂— bicyclo[1.1.1]pentanyl-CH₂—O—, and n is 0; and    -   A is unsubstituted thiophenyl, or    -   A is

wherein

-   -   R⁵ and R⁹ are independently H or halo,    -   Z′ is N or CR⁶,    -   Z is N or CR⁸,    -   wherein R⁶ and R⁸ are independently selected from the group        consisting of H, CN, halo, C₁₋₃alkyl, C₁₋₃haloalkyl,        —S(O)₂—C₁₋₃alkyl and —S(O)—C₁₋₃alkyl, and    -   V is N or CR⁷, wherein R⁷ is selected from the group consisting        of H, halo, CN, C₁₋₃alkyl, C₁₋₃ alkyl, C₁₋₃haloalkyl, and        —S(O)₂—C₁₋₃alkyl, or R⁷ is -Q-(CH₂)_(m)—W, wherein        -   Q is O, N, or CH₂,        -   m is 0 or 1, and        -   W is selected from the group consisting of C₃₋₆ cycloalkyl,            heterocyclyl, 5 or 6 membered heteroaryl and phenyl, wherein            said cycloalkyl, heterocyclyl, heteroaryl or phenyl is            optionally substituted with one or more (e.g., one, or one            or two) substituents independently selected from the group            consisting of C₁₋₃haloalkyl, CN, halo and C₁₋₅ alkyl;    -   or when Z or Z′ is CR⁶ and V is CR⁷, R⁶ and R⁷ together may form        a 4,7-dioxaspiro[2.6]nonane,

In a further embodiment, the present invention provides compounds ofFormula (II-4) and pharmaceutically acceptable salts thereof

wherein

-   -   R¹ and R² together with the nitrogen and carbon to which they        are attached form a 6-membered heterocyclic saturated ring,        which ring        -   optionally contains one or two additional heteroatom ring            member independently selected from the group consisting of            N, O, C(O), S, S(O), and S(O)₂, and        -   is optionally substituted with one or more (e.g., one, or            one or two) substituents independently selected from the            group consisting of OH, halo, NR^(1a)R^(1b), COOH, and            —Y—R^(c), wherein            -   Y is absent or is selected from the group consisting of                C(O), S(O)₂, —C(O)—C(O)—, and CH₂, and            -   R^(c) is selected from the group consisting of                -   C₁₋₅alkyl optionally substituted with one or more                    (e.g., one, one or two, or one, two or three)                    substituents independently selected from the group                    consisting of NR^(2a)R^(2b), C₃₋₆ cycloalkyl, and                    —COOH,                -   C₁₋₃haloalkyl,                -   C₁₋₃alkoxyl,                -   NR^(3a)R^(3b),                -   —(CH₂)_(p)—C(O)—O—C₁₋₃alkyl, wherein p is 1, 2, or 3                    and the —(CH₂)_(p)— is optionally substituted by one                    or more (e.g., one or one or two) methyl,                -   —(CH₂)_(q)—C₃₋₆ cycloalkyl, wherein q is 1, 2, or 3,                    wherein the cycloalkyl is optionally substituted                    with NR^(4a)R^(4b) and the —(CH₂)_(q)— is optionally                    substituted by one or more (e.g., one or one or two)                    methyl, and                -   heterocyclyl optionally substituted with one or more                    (e.g., one or one or two) substituents independently                    selected from the group consisting of halo and                    NR^(5a)R^(5b),        -   wherein R^(1a), R^(1b), R^(2a), R^(2b), R^(3a), R^(3b),            R^(4a), R^(4b), R^(5a), and R^(5b) are independently H or            C₁₋₃alkyl; and    -   R³ is H;    -   each occurrence of R⁴ is independently H or D;    -   X is absent or is selected from the group consisting of        -   —O—,        -   —NH—, and        -   —N(C₁₋₃ alkyl)-,    -   n is 0, 1 or 2;    -   or X is —O—CH₂— bicyclo[1.1.1]pentanyl-CH₂—O— and n is 0; and    -   A is unsubstituted thiophenyl, or    -   A is

wherein

-   -   R⁵ and R⁹ are independently H or halo,    -   Z′ is N or CR⁶,    -   Z is N or CR⁸,    -   wherein R⁶ and R⁸ are independently selected from the group        consisting of H, CN, halo, C₁₋₃alkyl, C₁₋₃haloalkyl,        —S(O)₂—C₁₋₃alkyl and —S(O)—C₁₋₃alkyl, and    -   V is N or CR⁷, wherein R⁷ is selected from the group consisting        of H, halo, CN, C₁₋₃alkyl, C₁₋₃ alkyl, C₁₋₃haloalkyl, and        —S(O)₂—C₁₋₃alkyl, or R⁷ is -Q-(CH₂)_(m)—W, wherein        -   Q is O, N, or CH₂,        -   m is 0 or 1, and        -   W is selected from the group consisting of C₃₋₆ cycloalkyl,            heterocyclyl, 5 or 6 membered heteroaryl and phenyl, wherein            said cycloalkyl, heterocyclyl, heteroaryl or phenyl is            optionally substituted with one or more (e.g., one, or one            or two) substituents independently selected from the group            consisting of C₁₋₃haloalkyl, CN, halo and C₁₋₅ alkyl;    -   or when Z or Z′ is CR⁶ and V is CR⁷, R⁶ and R⁷ together may form        a 4,7-dioxaspiro[2.6]nonane,

with the proviso that the compound of Formula (II-4) is not

-   2-fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile,-   7-(2,3-difluorophenethyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one,-   7-((2,3-difluorobenzyl)amino)-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione,-   7-((3,4-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one    2,2-dioxide,-   7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one-2-oxide,-   7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one-2,2-dioxide,    or-   7-(2,3-difluorophenethyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one.

In a further embodiment, the present invention provides compounds ofFormula (II-5) and pharmaceutically acceptable salts thereof

wherein

-   -   R¹ and R² together with the nitrogen and carbon to which they        are attached form a 6-membered heterocyclic saturated ring,        which ring        -   optionally contains one or two additional heteroatom ring            member independently selected from the group consisting of            N, O, C(O), S, S(O), and S(O)₂, and        -   is optionally substituted with one or more (e.g., one, or            one or two) substituents independently selected from the            group consisting of OH, halo, NR^(1a)R^(1b), COOH, and            —Y—R^(c), wherein            -   Y is absent or is selected from the group consisting of                C(O), S(O)₂, —C(O)—C(O)—, and CH₂, and            -   R^(c) is selected from the group consisting of                -   C₁₋₅alkyl optionally substituted with one or more                    (e.g., one, one or two, or one, two or three)                    substituents independently selected from the group                    consisting of NR^(2a)R^(2b), C₃₋₆ cycloalkyl, and                    —COOH,                -   C₁₋₃haloalkyl,                -   C₁₋₃alkoxyl,                -   NR^(3a)R^(3b),                -   —(CH₂)_(p)—C(O)—O—C₁₋₃alkyl, wherein p is 1, 2, or 3                    and the —(CH₂)_(p)— is optionally substituted by one                    or more (e.g., one or one or two) methyl,                -   —(CH₂)_(q)—C₃₋₆ cycloalkyl, wherein q is 1, 2, or 3,                    wherein the cycloalkyl is optionally substituted                    with NR^(4a)R^(4b) and the —(CH₂)_(q)— is optionally                    substituted by one or more (e.g., one or one or two)                    methyl, and                -   heterocyclyl optionally substituted with one or more                    (e.g., one or one or two) substituents independently                    selected from the group consisting of halo and                    NR^(5a)R^(5b),        -   wherein R^(1a), R^(1b), R^(2a), R^(2b), R^(3a), R^(3b),            R^(4a), R^(4b), R^(5a), and R^(5b) are independently H or            C₁₋₃alkyl; and    -   R³ is H;    -   each occurrence of R⁴ is independently H or D;    -   X is absent or is selected from the group consisting of        -   —O—,        -   —NH—, and        -   —N(C₁₋₃ alkyl)-,    -   n is 0, 1 or 2;    -   or X is —O—CH₂— bicyclo[1.1.1]pentanyl-CH₂—O—, and n is 0; and    -   A is unsubstituted thiophenyl, or    -   A is

wherein

-   -   R⁵ and R⁹ are independently H or halo,    -   Z′ is N or CR⁶,    -   Z is N or CR⁸,    -   wherein R⁶ and R⁸ are independently selected from the group        consisting of H, CN, halo, C₁₋₃alkyl, C₁₋₃haloalkyl,        —S(O)₂—C₁₋₃alkyl and —S(O)—C₁₋₃alkyl, and    -   V is N or CR⁷, wherein R⁷ is selected from the group consisting        of H, halo, CN, C₁₋₃alkyl, C₁₋₃ alkyl, C₁₋₃haloalkyl, and        —S(O)₂—C₁₋₃alkyl, or R⁷ is -Q-(CH₂)_(m)—W, wherein        -   Q is O, N, or CH₂,        -   m is 0 or 1, and        -   W is selected from the group consisting of C₃₋₆ cycloalkyl,            heterocyclyl, 5 or 6 membered heteroaryl and phenyl, wherein            said cycloalkyl, heterocyclyl, heteroaryl or phenyl is            optionally substituted with one or more (e.g., one, or one            or two) substituents independently selected from the group            consisting of C₁₋₃haloalkyl, CN, halo and C₁₋₅ alkyl;    -   or when Z or Z′ is CR⁶ and V is CR⁷, R⁶ and R⁷ together may form        a 4,7-dioxaspiro[2.6]nonane,

with the proviso that the compound of Formula (II-5) is not

-   2-fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile,-   7-(2,3-difluorophenethyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one,-   7-((2,3-difluorobenzyl)amino)-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione,-   7-((3,4-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one    2,2-dioxide,-   7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one-2-oxide,-   7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one-2,2-dioxide,    or-   7-(2,3-Difluorophenethyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one,

and the compound of Formula (II-5) is not

-   -   wherein    -   R^(I) is H or F;    -   R^(II) is selected from the group consisting of H, halo, CN, and        CF₃;    -   R^(III) is selected from the group consisting of H, F, CN, CF₃,        CH₃, and —O—Y, wherein    -   Y is a phenyl, pyridinyl or pyrimidinyl, wherein the phenyl,        pyridinyl or pyrimidinyl is substituted with one or more        substituents independently selected from the group consisting of        halo, CF₃ and CN; and    -   R^(IV) is selected from the group consisting of CN, H, F and        CH₃.

In other embodiments, the present invention provides compounds ofFormula (III-1) and pharmaceutically acceptable salts thereof,

wherein

-   -   R¹ and R² together with the nitrogen and carbon to which they        are attached form a 5 or 6-membered heterocyclic saturated,        unsubstituted ring, which ring optionally contains one        additional heteroatom ring member selected from N, O and C(O);        and    -   R³ is H;    -   R⁴ is H;    -   X is O;    -   n is 1 or 2; and    -   A is

wherein

-   -   R⁵ and R⁹ are independently H or halo,    -   Z′ is N or CR⁶,    -   Z is N or CR⁸,        -   wherein R⁶ and R⁸ are independently selected from the group            consisting of H, CN, halo, C₁₋₃alkyl, C₁₋₃haloalkyl,            —S(O)₂—C₁₋₃alkyl and —S(O)—C₁₋₃alkyl, and    -   V is N or CR⁷, wherein R⁷ is selected from the group consisting        of H, halo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, and —S(O)₂—C₁₋₃alkyl,        or R⁷ is -Q-(CH₂)_(m)—W, wherein        -   Q is O, N, or CH₂,        -   m is 0 or 1, and        -   W is selected from the group consisting of C₃₋₆cycloalkyl,            heterocyclyl, 5 or 6 membered heteroaryl and phenyl, wherein            said cycloalkyl, heterocyclyl, heteroaryl or phenyl is            optionally substituted with one or more (e.g., one, or one            or two) substituents independently selected from the group            consisting of C₁₋₃haloalkyl, CN, halo and C₁₋₅ alkyl,

with the proviso that the compound of Formula (III-1) is not

-   2-fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile    or-   7-(2,3-difluorophenethyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one.

In other embodiments, the present invention provides compounds ofFormula (III-2) and pharmaceutically acceptable salts thereof,

wherein

-   -   R¹ and R² together with the nitrogen and carbon to which they        are attached form a 5 or 6-membered heterocyclic saturated,        unsubstituted ring, which ring optionally contains one        additional heteroatom ring member selected from N, O and C(O);        and    -   R³ is H;    -   R⁴ is H;    -   X is O;    -   n is 1 or 2; and    -   A is

wherein

-   -   R⁵ and R⁹ are independently H or halo,    -   Z′ is N or CR⁶,    -   Z is N or CR⁸,        -   wherein R⁶ and R⁸ are independently selected from the group            consisting of H, CN, halo, C₁₋₃alkyl, C₁₋₃haloalkyl,            —S(O)₂—C₁₋₃alkyl and —S(O)—C₁₋₃alkyl, and    -   V is N or CR⁷, wherein R⁷ is selected from the group consisting        of H, halo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, and —S(O)₂—C₁₋₃alkyl,        or R⁷ is -Q-(CH₂)_(m)—W, wherein        -   Q is O, N, or CH₂,        -   m is 0 or 1, and        -   W is selected from the group consisting of C₃₋₆cycloalkyl,            heterocyclyl, 5 or 6 membered heteroaryl and phenyl, wherein            said cycloalkyl, heterocyclyl, heteroaryl or phenyl is            optionally substituted with one or more (e.g., one, or one            or two) substituents independently selected from the group            consisting of C₁₋₃haloalkyl, CN, halo and C₁₋₅ alkyl,

with the proviso that the compound of Formula (III-2) is not

-   2-fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile    or-   7-(2,3-difluorophenethyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one,

and with the proviso that the compound of Formula (III-2) is not

-   -   wherein    -   R^(I) is H or F;    -   R^(II) is selected from the group consisting of H, halo, CN, and        CF₃;    -   R^(III) is selected from the group consisting of H, F, CN, CF₃,        CH₃, and —O—Y, wherein Y is a phenyl, pyridinyl or pyrimidinyl,        wherein the phenyl, pyridinyl or pyrimidinyl is substituted with        one or more substituents independently selected from the group        consisting of halo, CF₃ and CN; and    -   R^(IV) is selected from the group consisting of CN, H, F and        CH₃.

In other embodiments, the present invention provides compounds ofFormula (III-3) and pharmaceutically acceptable salts thereof,

wherein

-   -   R¹ and R² together with the nitrogen and carbon to which they        are attached form a 5-membered heterocyclic saturated,        unsubstituted ring, which ring optionally contains one        additional heteroatom ring member selected from N, O and C(O);        and    -   R³ is H;    -   R⁴ is H;    -   X is O;    -   n is 1 or 2; and    -   A is

wherein

-   -   R⁵ and R⁹ are independently H or halo,    -   Z′ is N or CR⁶,    -   Z is N or CR⁸,        -   wherein R⁶ and R⁸ are independently selected from the group            consisting of H, CN, halo, C₁₋₃alkyl, C₁₋₃haloalkyl,            —S(O)₂—C₁₋₃alkyl and —S(O)—C₁₋₃alkyl, and    -   V is N or CR⁷, wherein R⁷ is selected from the group consisting        of H, halo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, and —S(O)₂—C₁₋₃alkyl,        or R⁷ is -Q-(CH₂)_(m)—W, wherein        -   Q is O, N, or CH₂,        -   m is 0 or 1, and        -   W is selected from the group consisting of C₃₋₆cycloalkyl,            heterocyclyl, 5 or 6 membered heteroaryl and phenyl, wherein            said cycloalkyl, heterocyclyl, heteroaryl or phenyl is            optionally substituted with one or more (e.g., one, or one            or two) substituents independently selected from the group            consisting of C₁₋₃haloalkyl, CN, halo and C₁₋₅ alkyl.

In other embodiments, the present invention provides compounds ofFormula (III-4) and pharmaceutically acceptable salts thereof,

wherein

-   -   R¹ and R² together with the nitrogen and carbon to which they        are attached form a 6-membered heterocyclic saturated,        unsubstituted ring, which ring optionally contains one        additional heteroatom ring member selected from N, O and C(O);        and    -   R³ is H;    -   R⁴ is H;    -   X is O;    -   n is 1 or 2; and    -   A is

wherein

-   -   R⁵ and R⁹ are independently H or halo,    -   Z′ is N or CR⁶,    -   Z is N or CR⁸,        -   wherein R⁶ and R⁸ are independently selected from the group            consisting of H, CN, halo, C₁₋₃alkyl, C₁₋₃haloalkyl,            —S(O)₂—C₁₋₃alkyl and —S(O)—C₁₋₃alkyl, and    -   V is N or CR⁷, wherein R⁷ is selected from the group consisting        of H, halo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, and —S(O)₂—C₁₋₃alkyl,        or R⁷ is -Q-(CH₂)_(m)—W, wherein        -   Q is O, N, or CH₂,        -   m is 0 or 1, and        -   W is selected from the group consisting of C₃₋₆cycloalkyl,            heterocyclyl, 5 or 6 membered heteroaryl and phenyl, wherein            said cycloalkyl, heterocyclyl, heteroaryl or phenyl is            optionally substituted with one or more (e.g., one, or one            or two) substituents independently selected from the group            consisting of C₁₋₃haloalkyl, CN, halo and C₁₋₅ alkyl,

with the proviso that the compound of Formula (III-4) is not

-   2-fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile,    or-   7-(2,3-difluorophenethyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one.

In other embodiments, the present invention provides compounds ofFormula (III-5) and pharmaceutically acceptable salts thereof,

wherein

-   -   R¹ and R² together with the nitrogen and carbon to which they        are attached form a 6-membered heterocyclic saturated,        unsubstituted ring, which ring optionally contains one        additional heteroatom ring member selected from N, O and C(O);        and    -   R³ is H;    -   R⁴ is H;    -   X is O;    -   n is 1 or 2; and    -   A is

wherein

-   -   R⁵ and R⁹ are independently H or halo,    -   Z′ is N or CR⁶,    -   Z is N or CR⁸,        -   wherein R⁶ and R⁸ are independently selected from the group            consisting of H, CN, halo, C₁₋₃alkyl, C₁₋₃haloalkyl,            —S(O)₂—C₁₋₃alkyl and —S(O)—C₁₋₃alkyl, and    -   V is N or CR⁷, wherein R⁷ is selected from the group consisting        of H, halo, CN, C₁₋₃alkyl, C₁₋₃haloalkyl, and —S(O)₂—C₁₋₃alkyl,        or R⁷ is -Q-(CH₂)_(m)—W, wherein        -   Q is O, N, or CH₂,        -   m is 0 or 1, and        -   W is selected from the group consisting of C₃₋₆cycloalkyl,            heterocyclyl, 5 or 6 membered heteroaryl and phenyl, wherein            said cycloalkyl, heterocyclyl, heteroaryl or phenyl is            optionally substituted with one or more (e.g., one, or one            or two) substituents independently selected from the group            consisting of C₁₋₃haloalkyl, CN, halo and C₁₋₅ alkyl,

with the proviso that the compound of Formula (III-5) is not

-   2-fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile,    or-   7-(2,3-difluorophenethyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one,

and the compound of Formula (III-5) is not

-   -   wherein    -   R^(I) is H or F;    -   R^(II) is selected from the group consisting of H, halo, CN, and        CF₃;    -   R^(III) is selected from the group consisting of H, F, CN, CF₃,        CH₃, and —O—Y, wherein Y is a phenyl, pyridinyl or pyrimidinyl,        wherein the phenyl, pyridinyl or pyrimidinyl is substituted with        one or more substituents independently selected from the group        consisting of halo, CF₃ and CN; and    -   R^(IV) is selected from the group consisting of CN, H, F and        CH₃.

In other embodiments, the present invention provides compounds ofFormula Z and pharmaceutically acceptable salts thereof,

-   -   R^(I) is H or F;    -   R^(II) is selected from the group consisting of H, halo, CN, and        CF₃;    -   R^(III) is selected from the group consisting of H, F, CN, CF₃,        CH₃, and —O—Y,    -   wherein Y is a phenyl, pyridinyl or pyrimidinyl, wherein the        phenyl, pyridinyl or pyrimidinyl is substituted with one or more        substituents independently selected from the group consisting of        halo, CF₃ and CN; and    -   R^(IV) is selected from the group consisting of CN, H, F and        CH₃.    -   R⁴ is selected from the group consisting of CN, H, F and CH₃.

In one embodiment, this invention relates to compounds of abovereferenced Formulas and any of the above applicable embodiments, whereinR¹ and R² together with the nitrogen and carbon to which they areattached form a 5 or 6-membered heterocyclic saturated ring, which ringoptionally contains one additional heteroatom ring member selected fromN, O and C(O), and R³ is H, and pharmaceutically acceptable saltsthereof.

In one embodiment, this invention relates to compounds of abovereferenced Formulas and any of the above applicable embodiments, whereinR¹ and R² together with the nitrogen and carbon to which they areattached form a 5-membered heterocyclic saturated ring, which ringoptionally contains one additional heteroatom ring member selected fromN, O and C(O), and R³ is H, and pharmaceutically acceptable saltsthereof.

In one embodiment, this invention relates to compounds of abovereferenced Formulas and any of the above applicable embodiments, whereinR¹ and R² together with the nitrogen and carbon to which they areattached form a 6-membered heterocyclic saturated ring, which ringoptionally contains one additional heteroatom ring member selected fromN, O and C(O), and R³ is H, and pharmaceutically acceptable saltsthereof.

In one embodiment, this invention relates to compounds of abovereferenced Formulas and any of the above applicable embodiments, whereinR¹ and R² together with the nitrogen and carbon to which they areattached form a 6-membered heterocyclic saturated ring, which ringcontains one additional heteroatom ring member selected from N, O andC(O), and R³ is H, and pharmaceutically acceptable salts thereof.

In the other embodiment, this invention relates to compounds of abovereferenced Formulas and any of the above applicable embodiments, whereinR¹ and R² together with the nitrogen and carbon to which they areattached form a 5 or 6-membered heterocyclic saturated ring, which ringoptionally contains one additional heteroatom ring member selected fromN or O, and R³ is H, and pharmaceutically acceptable salts thereof.

In the other embodiment, this invention relates to compounds of abovereferenced Formulas and any of the above applicable embodiments, whereinR¹ and R² together with the nitrogen and carbon to which they areattached form a 5-membered heterocyclic saturated ring, which ringoptionally contains one additional heteroatom ring member selected fromN or O, and R³ is H, and pharmaceutically acceptable salts thereof.

In the other embodiment, this invention relates to compounds of abovereferenced Formulas and any of the above applicable embodiments, whereinR¹ and R² together with the nitrogen and carbon to which they areattached form a 6-membered heterocyclic saturated ring, which ringoptionally contains one additional heteroatom ring member selected fromN or O, and R³ is H, and pharmaceutically acceptable salts thereof.

In the other embodiment, this invention relates to compounds of abovereferenced Formulas and any of the above applicable embodiments, whereinR¹ and R² together with the nitrogen and carbon to which they areattached form a 6-membered heterocyclic saturated ring, which ringcontains one additional heteroatom ring member selected from N or O, andR³ is H, and pharmaceutically acceptable salts thereof.

In a further embodiment, this invention relates to compounds of abovereferenced Formulas and any of the above applicable embodiments, whereinR¹ and R² together with the nitrogen and carbon to which they areattached form a 5 membered, saturated heterocycle, which contain noadditional heteroatom ring member, which ring is optionally substitutedwith one substituent of —Y—R_(c), wherein Y is absent or C(O) and R^(c)is selected from the group consisting of C₁₋₃haloalkyl, unsubstitutedC₃₋₆cycloalkyl, and unsubstituted 5 or 6 membered heterocyclyl, and R³is H, and pharmaceutically acceptable salts thereof.

In a further embodiment, this invention relates to compounds of abovereferenced Formulas and any of the above applicable embodiments, whereinR¹ and R² together with the nitrogen and carbon to which they areattached form a 5 membered unsubstituted, saturated heterocycle, whichcontains no additional heteroatom ring member, and R³ is H, andpharmaceutically acceptable salts thereof.

In one embodiment, this invention relates to compounds of abovereferenced Formulas and any of the above applicable embodiments, whereinR⁴ is H and pharmaceutically acceptable salts thereof.

In one embodiment, this invention relates to compounds of abovereferenced Formulas and any of the above applicable embodiments, whereinX is O and pharmaceutically acceptable salts thereof.

In one embodiment, this invention relates to compounds of abovereferenced Formulas and any of the above applicable embodiments, whereinn is 1 and pharmaceutically acceptable salts thereof.

In one embodiment, this invention relates to compounds of abovereferenced Formulas and any of the above applicable embodiments andpharmaceutically acceptable salts thereof, wherein A is

wherein

-   -   R⁵ and R⁹ are independently H or F;    -   R⁶ and R⁸ are independently selected from the group consisting        of H, CN, and F; and    -   R⁷ is selected from the group consisting of H, F, CN, C₁₋₃        alkyl, and C₁₋₃haloalkyl,    -   or R⁷ is -Q-(CH₂)_(m)—W, wherein        -   Q is O,        -   m is 0 or 1, and            -   W is 5 or 6 membered heteroaryl or phenyl, wherein said                heteroaryl or phenyl is optionally substituted with one                or more substituents independently selected from the                group consisting of C₁₋₃haloalkyl, CN, halo and                C₁₋₅alkyl.

Further, in one embodiment, this invention relates to compounds of abovereferenced Formulas and any of the above applicable embodiments andpharmaceutically acceptable salts thereof, wherein A is

wherein

-   -   R⁵ and R⁹ are independently H or F;    -   R⁶ and R⁸ are independently selected from the group consisting        of H, CN, and F; and    -   R⁷ is selected from the group consisting of H, F, CN, C₁₋₃        alkyl, and C₁₋₃haloalkyl.

Yet, in another embodiment, this invention relates to compounds of abovereferenced Formulas and any of the above applicable embodiments andpharmaceutically acceptable salts thereof, wherein A is

wherein

-   -   R⁵ and R⁹ are independently H or F; and    -   R⁶ and R⁸ are independently selected from the group consisting        of H, CN, and F; and    -   R⁷ is —O—W, wherein W is 5 or 6 membered heteroaryl or phenyl,        wherein said heteroaryl or phenyl is optionally substituted with        one or more (e.g., one, or one or two) substituents        independently selected from the group consisting of        C₁₋₃haloalkyl, CN, halo and C₁₋₅alkyl.

In one embodiment, this invention relates to compounds of abovereferenced Formulas and any of the above applicable embodiments andpharmaceutically acceptable salts thereof, wherein A is

wherein

-   -   R⁵ and R⁹ are independently H or F;    -   R⁶ and R⁸ are independently selected from the group consisting        of H, CN, and F; and    -   R⁷ is selected from the group consisting of H, F, CN, C₁₋₃alkyl,        and C₁₋₃haloalkyl, or R⁷ is —O—W, wherein W is selected from the        group consisting of pyridinyl, pyrimidinyl, pyrazolyl and        phenyl, wherein said pyridinyl, pyrimidinyl, pyrazolyl or phenyl        is optionally substituted with one or more (e.g., one, or one or        two) substituents independently selected from the group        consisting of C₁₋₃haloalkyl and C₁₋₅alkyl.

In one embodiment, this invention relates to compounds of abovereferenced Formulas and any of the above applicable embodiments andpharmaceutically acceptable salts thereof, wherein A is

wherein

-   -   R⁵ and R⁹ are independently H or F;    -   R⁶ and R⁸ are independently selected from the group consisting        of H, CN, and F; and    -   R⁷ is —O—W, wherein W is pyridinyl, pyrimidinyl, pyrazolyl and        phenyl, wherein said pyridinyl, pyrimidinyl, pyrazolyl or phenyl        is optionally substituted with one or more (e.g., one, or one or        two) substituents independently selected from the group        consisting of CF₃ and CH₃.

In one embodiment, the compound for Formula (I) is a compound of Formula(A-1)

wherein

R¹ and R² together with the nitrogen and carbon to which they areattached form a 5 or 6-membered heterocyclic saturated ring, which ringoptionally contains one additional heteroatom ring member selected fromthe group consisting of N, O, and C(O), and which ring has no furthersubstitution;

R⁵ and R⁹ are independently H or F;

R⁶ and R⁸ are independently selected from the group consisting of H orF; and

W¹ is selected from the group consisting of pyridinyl, pyrimidinyl,pyrazolyl and phenyl, wherein said pyridinyl, pyrimidinyl, pyrazolyl orphenyl is optionally substituted with one or more (e.g., one, or one ortwo) substituents independently selected from the group consisting ofCF₃ and CH₃,

or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound for Formula (I) is a compound of Fomula(A-2)

wherein

R¹ and R² together with the nitrogen and carbon to which they areattached form a 5-membered heterocyclic saturated ring, which ringoptionally contains one additional heteroatom ring member selected fromthe group consisting of N, O, and C(O), and which ring has no furthersubstitution;

R⁵ and R⁹ are independently H or F;

R⁶ and R⁸ are independently selected from the group consisting of H orF; and

W¹ is selected from the group consisting of pyridinyl, pyrimidinyl,pyrazolyl and phenyl, wherein said pyridinyl, pyrimidinyl, pyrazolyl orphenyl is optionally substituted with one or more (e.g., one, or one ortwo) substituents independently selected from the group consisting ofCF₃ and CH₃,

or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound for Formula (I) is a compound of Formula(A-3)

wherein

-   -   R¹ and R² together with the nitrogen and carbon to which they        are attached form a 6-membered heterocyclic saturated ring,        which ring optionally contains one additional heteroatom ring        member selected from the group consisting of N, O, and C(O), and        which ring has no further substitution;    -   R⁵ and R⁹ are independently H or F;    -   R⁶ and R⁸ are independently selected from the group consisting        of H or F; and    -   W¹ is selected from the group consisting of pyridinyl,        pyrimidinyl, pyrazolyl and phenyl, wherein said pyridinyl,        pyrimidinyl, pyrazolyl or phenyl is optionally substituted with        one or more (e.g., one, or one or two) substituents        independently selected from the group consisting of CF₃ and CH₃,    -   or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound for Formula (I) is a compound of Formula(A-4)

wherein

-   -   R¹ and R² together with the nitrogen and carbon to which they        are attached form a 6-membered heterocyclic saturated ring,        which ring contains one additional heteroatom ring member        selected from the group consisting of N, O, and C(O), and which        ring has no further substitution;    -   R⁵ and R⁹ are independently H or F;    -   R⁶ and R⁸ are independently selected from the group consisting        of H or F; and    -   W¹ is selected from the group consisting of pyridinyl,        pyrimidinyl, pyrazolyl and phenyl, wherein said pyridinyl,        pyrimidinyl, pyrazolyl or phenyl is optionally substituted with        one or more (e.g., one, or one or two) substituents        independently selected from the group consisting of CF₃ and CH₃,    -   or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound for Formula (I) is a compound of Formula(A-5)

wherein

-   -   R¹ and R² together with the nitrogen and carbon to which they        are attached form a 6-membered heterocyclic saturated ring,        which ring contains one additional heteroatom ring member        selected from the group consisting of O and which ring has no        further substitution;    -   R⁵ and R⁹ are independently H or F;    -   R⁶ and R⁸ are independently selected from the group consisting        of H or F; and    -   W¹ is selected from the group consisting of pyridinyl,        pyrimidinyl, pyrazolyl and phenyl, wherein said pyridinyl,        pyrimidinyl, pyrazolyl or phenyl is optionally substituted with        one or more (e.g., one, or one or two) substituents        independently selected from the group consisting of CF₃ and CH₃,    -   or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound is

wherein

-   -   R¹ and R² together with the nitrogen and carbon to which they        are attached form a 5 or 6-membered heterocyclic saturated ring,        which ring optionally contains one additional heteroatom ring        member selected from the group consisting of N, O, and C(O), and        which ring has no further substitution;    -   R⁵ and R⁹ are independently H or F;    -   R⁶ and R⁸ are independently selected from the group consisting        of H or F;    -   W² is selected from the group consisting of H, halo, CN,        C₁₋₃alkyl, C₁₋₃ alkyl and C₁₋₃haloalkyl;    -   or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound is

wherein

-   -   R¹ and R² together with the nitrogen and carbon to which they        are attached form a 5 or 6-membered heterocyclic saturated ring,        which ring optionally contains one additional heteroatom ring        member of O, and which ring has no further substitution;    -   R⁵ and R⁹ are independently H or F;    -   R⁶ and R⁸ are independently selected from the group consisting        of H or F;    -   W² is selected from the group consisting of H, halo, C₁₋₃ alkyl        and C₁₋₃haloalkyl;    -   or a pharmaceutically acceptable salt thereof.

In one embodiment, the compound of Formula (I) is a compound of any oneof Examples 1 to 66, 68-70, 72-265, 267-317, 319-354, 356-375, 377, and381-412, a free base, free acid, or a salt (e.g., a pharmaceuticallyacceptable salt) thereof.

In one embodiment, the compound of Formula (I) is a compound of any oneof Examples 36, 44, 50-66, 68-70, 72-265, 267-317, 319-354, 356-375,377, and 381-412, a free base, free acid, or a salt (e.g., apharmaceutically acceptable salt) thereof.

In one embodiment, the compound of Formula (I) is a compound of any oneof Examples 1-35, 37-43 and 45-49, a free base, free acid, or a salt(e.g., a pharmaceutically acceptable salt) thereof.

In one embodiment, the compound of Formula (I) is a compound of any oneof below compounds:

-   3-((3,4-difluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one,-   3-((3,4,5-trifluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one,-   3-(((1-oxo-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-3-yl)    oxy)methyl)benzonitrile,-   3-((4-fluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo-[1,2-c]    pyrimidin-1-one,-   3-((3,5-difluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one,-   3-(2-(thiophen-2-yl)ethoxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one,-   3-((3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one,-   3-((3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one,-   3-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one,-   3-((3-fluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one,-   3-((3-fluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]    pyrimidin-1-one,-   3-((3,5-difluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]    pyrimidin-1-one,-   3-((2,4-difluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]    pyrimidin-1-one,-   3-((2,3-difluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]    pyrimidin-1-one,-   3-((2,4,5-trifluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one,-   3-((2,4-difluorobenzyl)(methyl)amino)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]    imidazo[1,2-c]pyrimidin-1-one,-   3-((3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one,-   3-((3, 5-difluoro-4-((1-methyl-1H-pyrazol-4-yl) oxy) benzyl) oxy)-7,    8, 8a, 9-tetrahydro pyrrolo    [1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((3, 5-difluoro-4-((2-(trifluoromethyl) pyridin-4-yl) oxy) benzyl)    oxy)-7, 8, 8a, 9-tetra    hydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((3-fluoro-4-((1-methyl-1H-pyrazol-4-yl) oxy) benzyl) oxy)-7, 8,    8a, 9-tetrahydro    pyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((3-fluoro-4-((2-(trifluoromethyl) pyrimidin-5-yl) oxy) benzyl)    oxy)-7, 8, 8a, 9-tetra    hydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((3,4,5-trifluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((4-(3,4-difluorophenoxy)-3,5-difluorobenzyl)oxy)-7,8,8a,    9-tetrahydropyrrolo [1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro    pyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((3,5-difluoro-4-(3-(trifluoromethyl)phenoxy)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo    [1′,2′:3, 4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((6-(4-fluoro-3-(trifluoromethyl)phenoxy)pyridin-3-yl)methoxy)-7,8,8a,9-tetrahydro    pyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   2-(3-fluorophenoxy)-5-(((1-oxo-1,6,7,8,8a,9-hexahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]    pyrimidin-3-yl)oxy)methyl)benzonitrile,-   2-(3,5-difluorophenoxy)-5-(((1-oxo-1,6,7,8,8a,9-hexahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]    pyrimidin-3-yl)oxy)methyl)benzonitrile,-   3-((3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((4-((3,3-difluorocyclohexyl)oxy)-3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo    [1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((4-((3,3-difluorocyclopentyl)oxy)-3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((3,5-difluoro-4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)oxy)benzyl)oxy)-7,8,8a,9-tetra    hydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((2,4-difluorobenzyl)oxy)-7,8,8a,    9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((2, 3-difluorobenzyl) oxy)-7, 8, 8a, 9-tetrahydropyrrolo    [1′,2′:3, 4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((3-fluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((3,5-difluorobenzyl)oxy)-7,8,8a,    9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((3-fluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)benzyl)oxy)-7,8,8a,9-tetrahydro    pyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro    pyrrolo [1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   7-((3,5-difluoro-4-((1-propyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-3,4,11,11atetrahydro    pyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one,-   7-((3, 5-difluoro-4-((2-(trifluoromethyl) pyridin-4-yl) oxy) benzyl)    oxy)-3, 4, 11, 11a tetrahydro    pyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one,-   7-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-3,4,11,11a-tetrahydro    pyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one,-   7-((4-((1-ethyl-1H-pyrazol-4-yl)oxy)-3,5-difluorobenzyl)oxy)-3,4,11,11a-tetrahydro    pyrimido [6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one,-   7-((3,4,5-trifluorobenzyl)oxy)-3,4,11,11atetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]    oxazin-9(1H)-one,-   7-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-3,4,11,11atetrahydropyrimido    [6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one,-   7-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-3,4,11,11atetrahydropyrimido    [6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one,-   7-((3, 5-difluoro-4-((2-(trifluoromethyl)    pyridin-4-yl)oxy)benzyl)oxy)-3, 4, 11, 11a-tetra    hydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one,-   7-((2,4-difluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]    oxazin-9(1H)-one,-   7-((2,3-difluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]    oxazin-9(1H)-one,-   7-((3-fluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one,-   7-((3,5-difluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]    oxazin-9(1H)-one,-   3-((3,5-difluoro-4-((2-(trifluoromethyl)    pyridin-4-yl)oxy)benzyl)oxy)-8,9,9a,10-tetrahydro    pyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one,-   3-((3,5-difluoro-4-((2-(trifluoromethyl)    pyridin-4-yl)oxy)benzyl)oxy)-8,9,9a,10-tetrahydr    opyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one,-   3-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-8,9,9a,10-tetrahydropyri-mdo[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one,-   3-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-8,9,9a,10-tetrahydro    pyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one,-   3-((3-fluorobenzyl)oxy)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one,-   3-((3,4,5-trifluorobenzyl)oxy)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]    oxazin-1(6H)-one,-   3-((3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)benzyl)oxy)-8,9,9a,10-tetrahydro    pyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one,-   6-((3,5-difluoro-4-((2-(trifluoromethyl)    pyridin-4-yl)oxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   6-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   6-((4-chloro-3-fluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]    pyrimidin-8(3H)-one,-   6-((3,4,5-trifluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   6-((3,5-difluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   6-((3-fluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   6-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo    [3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   6-((3,5-difluoro-4-((1-propyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   6-((3,5-difluoro-4-((1-(trifluoromethyl)-1H-pyrazol-4-yl)oxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   6-((3,5-difluoro-4-((2-methylpyrimidin-5-yl)oxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo    [3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   6-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo    [3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   6-((4-((1-ethyl-1H-pyrazol-4-yl)oxy)-3,5-difluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo    [3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   6-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   7-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-3,4,11,    11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-b][1,3]oxazin-9(2H)-one,-   6-((3,5-difluoro-4-((2-(trifluoromethyl)    pyridin-4-yl)oxy)benzyl)oxy)-10,10a-dihydro-2H-oxazolo[3′,2′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   6-((2,4-difluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   6-((2,3-difluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimid    in-8(3H)-one,-   6-((2,3-difluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   6-((2,4,5-trifluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   6-((2,4-difluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidi-n-8(3H)-one,-   3-((2,4-difluorobenzyl)oxy)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]    oxazin-1(6H)-one,-   6-((3-(((2-(trifluoromethyl)    pyridin-4-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)methoxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   3-((2,4-difluorobenzyl)oxy)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one,-   3-((2,4,5-trifluorobenzyl)oxy)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one,-   3-((3,5-difluorobenzyl)oxy)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]    oxazin-1(6H)-one,-   3-((2,3-difluorobenzyl)oxy)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]    oxazin-1(6H)-one,-   6-(3-fluorophenethoxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   6-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-10,10a-dihydro-2H-oxazolo[3′,2′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   4-(2-((8-oxo-3,8,10,10a-tetrahydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-6-yl)oxy)ethyl)benzonitrile,-   3-(3-fluorophenethyl)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one,-   6-((3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   6-((9-fluoro-3,4-dihydrospiro[benzo[b][1,4]dioxepine-2,1′-cyclopropan]-7-yl)methoxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   3-((9-fluoro-3,4-dihydrospiro[benzo[b][1,4]dioxepine-2,1′-cyclopropan]-7-yl)methoxy)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one,-   6-(3-fluorophenethyl)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   6-(2,4-difluorophenethyl)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one,-   3-((4-((3,3-difluoropiperidin-1-yl)methyl)-3-fluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one,-   3-((4-((4,4-difluorocyclohexyl)oxy)-3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydro    pyrrolo [1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((4-((1-butylazetidin-3-yl)oxy)-3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo    [1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((3,5-difluoro-4-(3-fluoropropyl)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((3,5-difluoro-4-(2-fluoroethoxy)benzyl)oxy)-7,8,8a,    9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((2,3-difluorobenzyl)oxy)-7,8,8a,    9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((2,4,5-trifluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((3,5-difluorobenzyl)oxy)-7,8,8a,    9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((2,4-difluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((3,5-difluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((2,4,5-trifluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   7-((2,4,5-trifluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c]    [1,4]oxazin-9(1H)-one,-   7-((2,4,5-trifluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c]    [1,4]oxazin-9(1H)-one,-   7-((2,3-difluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one,-   3-((3,5-difluorobenzyl)(methyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((2,4-difluorobenzyl)(methyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo    [1,2-c]pyrimidin-1(6H)-one,-   3-(3-fluorophenethyl)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((2,4,5-trifluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((3,5-difluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((2,3-difluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((3,4,5-trifluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((2,4-difluorobenzyl)amino)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one,-   3-((3-fluorobenzyl)amino)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]    pyrimidin-1-one,-   3-((3,5-difluorobenzyl)amino)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one,-   3-((2,4,5-trifluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((3,4,5-trifluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((2,3-difluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((3-fluorobenzyl)(methyl)amino)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo    [1,2-c]pyrimidin-1-one,-   7-((2,4,5-trifluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one,-   7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c]    [1,4]oxazin-9(1H)-one,-   3-((2,4,5-trifluorobenzyl)amino)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo    [1,2-c]pyrimidin-1-one,-   3-((2,3-difluorobenzyl)amino)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one,-   7-(3-fluorophenethoxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one,-   3-(3-fluorophenethoxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-(methyl(2,4,5-trifluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo-   [1,2-c]pyrimidin-1(6H)-one,-   3-(methyl(3,4,5-trifluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((3-fluorobenzyl)(methyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((2,4-difluorobenzyl)(methyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   4-(2-((1-oxo-1,6,7,8,8a,9-hexahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)    ethyl)benzonitrile,-   4-(2-((9-oxo-1,3,4,9,11,11a-hexahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-7-yl)oxy)ethyl)benzonitrile,-   7-(3-fluorophenethyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one,-   7-(3-fluorophenethyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one,-   7-((3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)benzyl)oxy)-3,4,11,11a-tetrahydro    pyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one-   7-((9-fluoro-3,4-di    hydrospiro[benzo[b][1,4]dioxepine-2,1′-cyclopropan]-7-yl)methoxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one,-   3-((9-fluoro-3,4-di    hydrospiro[benzo[b][1,4]dioxepine-2,1′-cyclopropan]-7-yl)methoxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   3-((9-fluoro-3,4-di    hydrospiro[benzo[b][1,4]dioxepine-2,1′-cyclopropan]-7-yl)methoxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one,-   7-(2,4-difluorophenethyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]    oxazin-9(1H)-one,-   2-(azetidine-2-carbonyl)-7-((3,4-difluorobenzyl)oxy)-3,4,11,11a-tetrahydro-1H-pyrazino    [1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one,-   2-fluoro-5-((((7,8a)-7-hydroxy-1-oxo-1,6,7,8,8a,9-hexahydropyrrolo[1′,2′:3,4]imidazo    [1,2-c]pyrimidin-3-yl)oxy)methyl)benzonitrile,-   (7,8a)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7-hydroxy-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   (7,8a)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-7-hydroxy-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   5-((((7,8a)-7-Amino-1-oxo-1,6,7,8,8a,9-hexahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)-2-fluorobenzonitrile,-   (7,8a)-7-amino-3-((3,5-difluoro-4-((2-(trifluoromethyl)    pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   5-((((7,8a)-7-amino-1-oxo-1,6,7,8,8a,9-hexahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)-2-fluorobenzonitrile,-   (7,8a)-7-amino-3-((3,5-difluoro-4-((2-(trifluoromethyl)    pyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one,-   7-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-1-methyl-1H-spiro[imidazo[1,2-c]pyrimidine-2,3′-oxetan]-5(3H)-one,    a free base, free acid, or a salt (e.g., a pharmaceutically    acceptable salt) thereof.

The compounds of the above referenced formulas, salts (e.g.,pharmaceutically acceptable salts) thereof may exist in stereoisomericforms (e.g., it contains one or more asymmetric carbon atoms). Theindividual stereoisomers (enantiomers and diastereomers) and mixtures ofthese are included within the scope of the present invention. Theinvention also covers the individual isomers of the compounds of theabove referenced formulas, salts (e.g., pharmaceutically acceptablesalts) thereof as mixtures with isomers thereof in which one or morechiral centers are inverted. Likewise, it is understood that thecompounds of the above referenced formulas, salts (e.g.,pharmaceutically acceptable salts) thereof may exist in tautomeric formsother than that shown in the formula and these are also included withinthe scope of the present invention. It is to be understood that thepresent invention includes all combinations and subsets of theparticular groups defined hereinabove. The scope of the presentinvention includes mixtures of stereoisomers as well as purifiedenantiomers or enantiomerically/diastereomerically enriched mixtures.Also included within the scope of the invention are individual isomersof the compounds of the above referenced formulas, salts (e.g.,pharmaceutically acceptable salts) thereof, as well as any wholly orpartially equilibrated mixtures thereof. The present invention alsoincludes the individual isomers of the compounds of the above referencedformulas, salts (e.g., pharmaceutically acceptable salts) thereof aswell as mixtures with isomers thereof in which one or more chiralcenters are inverted. It is to be understood that the present inventionincludes all combinations and subsets of the particular groups definedhereinabove. The different isomeric forms may be separated or resolvedone from the other by conventional methods (e.g. chiral HPLC), or anygiven isomer may be obtained by conventional synthetic methods e.g.stereospecific or asymmetric syntheses.

The invention also includes various deuterated forms of compounds of theabove referenced formulas, salts (e.g., pharmaceutically acceptablesalts) thereof. Each available hydrogen atom attached to a carbon atommay be independently replaced with a deuterium atom. A person ofordinary skill in the art will know how to synthesize deuterated formsof compounds of the above referenced formulas, salts (e.g.,pharmaceutically acceptable salts) thereof. Commercially availabledeuterated starting materials may be employed in the preparation ofdeuterated forms of compounds of the above referenced formulas, salts(e.g., pharmaceutically acceptable salts) thereof, or they may besynthesized using conventional techniques employing deuterated reagents(e.g. lithium aluminum deuteride).

In addition to the free base or free acid form of the compoundsdescribed herein, the salt form of the compounds is also within thescope of the present invention. The salts or pharmaceutically-acceptablesalts of the compounds described herein may be prepared in situ duringthe final isolation and purification of the compound, or by separatelyreacting the purified compound in its free acid or free base form with asuitable base or acid, respectively. For reviews on suitablepharmaceutical salts see Berge et al, J. Pharm, Sci., 66, 1-19, 1977; PL Gould, International Journal of Pharmaceutics, 33 (1986), 201-217; andBighley et al, Encyclopedia of Pharmaceutical Technology, Marcel DekkerInc, New York 1996, Volume 13, page 453-497.

In certain embodiments, compounds of the present invention may containan acidic functional group, which is acidic enough to form salts.Representative salts include pharmaceutically-acceptable metal saltssuch as sodium, potassium, lithium, calcium, magnesium, aluminum, andzinc salts; carbonates and bicarbonates of a pharmaceutically acceptablemetal cation such as sodium, potassium, lithium, calcium, magnesium,aluminum, and zinc; pharmaceutically-acceptable organic primary,secondary, and tertiary amines including aliphatic amines, aromaticamines, aliphatic diamines, and hydroxy alkylamines such as methylamine,ethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine,diethanolamine, and cyclohexylamine.

In certain embodiments, compounds of the present invention may contain abasic group and are therefore capable of forming pharmaceuticallyacceptable acid addition salts by treatment with a suitable acid.Suitable acids include pharmaceutically-acceptable inorganic acids andpharmaceutically acceptable organic acids. These salts may becrystalline or amophorus. Exemplary pharmaceutically acceptable acidaddition salts include hydrochloride, hydrobromide, nitrate,methylnitrate, sulfate, bisulfate, sulfamate, phosphate, acetate,hydroxyacetate, phenylacetate, propionate, butyrate, isobutyrate,valerate, maleate, hydroxymaleate, acrylate, fumarate, malate, tartrate,citrate, salicylate, p-aminosalicyclate, glycollate, lactate,heptanoate, phthalate, oxalate, succinate, benzoate, o-acetoxybenzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate,methoxybenzoate, mandelate, tannate, formate, stearate, ascorbate,palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate,glutamate, estolate, methanesulfonate (mesylate), ethanesulfonate(esylate), 2-hydroxyethanesulfonate, benzenesulfonate (besylate),p-aminobenzenesulfonate, p-toluenesulfonate (tosylate), andnapthalene-2-sulfonate. In some embodiments, the pharmaceuticallyacceptable salts include the L-tartrate, ethanedisulfonate (edisylate),sulfate, phosphate, p-toluenesulfonate (tosylate), hydrochloride salt,methanesulfonate, citrate, fumarate, benzenesulfonate, maleate,hydrobromate, L-lactate, malonate, and S-camphor-10-sulfonate. Some ofthese salts form solvates, some are crystalline.

The compounds described herein, their salts (e.g., pharmaceuticallyacceptable salts), deuterated form, solvates or hydrates thereof, mayexist in one or more polymorphic form. Therefore, in a further aspect,the invention provides a polymorph of a compound defined herein, theirsalts (e.g., pharmaceutically acceptable salts), or a polymorph of asolvate or hydrate of a compound described herein or a salt (e.g.,pharmaceutically acceptable salt) thereof.

The compounds of the above referenced formulas and salts (includingpharmaceutically acceptable salts) thereof may be in the form of asolvate. For solvates of the compounds of the above referenced formulas,including solvates of salts of the compounds of the above referencedformulas, that are in crystalline form, the skilled artisan willappreciate that pharmaceutically acceptable solvates may be formedwherein solvent molecules are incorporated into the crystalline latticeduring crystallization. Solvates may involve nonaqueous solvents such asethanol, isopropanol, dimethylsulfoxide, acetic acid, ethanolamine, andethyl acetate, or they may involve water as the solvent that isincorporated into the crystalline lattice. Solvates wherein water is thesolvent that is incorporated into the crystalline lattice are typicallyreferred to as “hydrates.” Solvates include stoichiometric solvates aswell as compositions containing variable amounts of the incorporatedsolvent(s), e.g. a hydrate includes stoichiometric hydrates andcompositions containing variable amounts of water.

The invention also includes isotopically labeled compounds and salts,which are identical to compounds of the above referenced formulas orsalts thereof, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number most commonly found in nature. Examples of isotopesthat can be incorporated into compounds of the above referenced formulasor salts thereof isotopes of hydrogen, carbon, nitrogen, fluorine, suchas ³H, ¹¹C, ¹⁴C and ¹⁸F. Such isotopically-labeled compound of the abovereferenced formulas or salts thereof are useful in drug and/or substratetissue distribution assays. For example, ¹¹C and ¹⁸F isotopes are usefulin PET (positron emission tomography). PET is useful in brain imaging.Isotopically-labeled compounds of the above referenced formulas andsalts thereof can generally be prepared by carrying out the proceduresdisclosed below, by substituting a readily availableisotopically-labeled reagent for a non-isotopically labeled reagent. Inone embodiment, compounds of the above referenced formulas or saltsthereof are not isotopically labeled.

As used herein, the terms “compound(s) of the invention” or “compound(s)of the present invention” mean a compound of the above referencedformulas, as defined herein, in any form, i.e., any salt or non-saltform (e.g., as a free acid or base form, or as a salt, for example, apharmaceutically acceptable salt thereof), deuterated form and anyphysical form thereof (e.g., including non-solid forms (e.g., liquid orsemi-solid forms), and solid forms (e.g., amorphous or crystallineforms, specific polymorphic forms, solvate forms, including hydrateforms (e.g., mono-, di- and hemi-hydrates)), and mixtures of variousforms. In the context of pharmaceutical composition and methods oftreatment discussed herein, the terms of “compounds of the invention”mean a compound of the above referenced formulas, as defined herein, inthe form of any pharmaceutically acceptable salt thereof or non-saltform (e.g., as a free acid or base form), deuterated form and anyphysical form thereof (e.g., including non-solid forms (e.g., liquid orsemi-solid forms), and solid forms (e.g., amorphous or crystallineforms, specific polymorphic forms, solvate forms, including hydrateforms (e.g., mono-, di- and hemi-hydrates)), and mixtures of variousforms.

Accordingly, a compound of the invention includes a compound of theabove referenced formulas, or a salt thereof, for example apharmaceutically acceptable salt thereof. Representative compounds ofthis invention include the specific compounds described.

C. Synthesis of Compounds

The process to be utilized in the preparation of the compounds describedherein depends upon the desired compounds. Such factors as the selectionof the specific substituent and various possible locations of thespecific substituent all play a role in the path to be followed in thepreparation of the specific compounds of this invention. Those factorsare readily recognized by one of ordinary skill in the art.

The skilled artisan will appreciate that if a substituent describedherein is not compatible with the synthetic methods described herein,the substituent may be protected with a suitable protecting group thatis stable to the reaction conditions. The protecting group may beremoved at a suitable point in the reaction sequence to provide adesired intermediate or target compound. Suitable protecting groups andthe methods for protecting and de-protecting different substituentsusing such suitable protecting groups are well known to those skilled inthe art; examples of which may be found in T. Greene and P. Wuts,Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY(1999). In some instances, a substituent may be specifically selected tobe reactive under the reaction conditions used. Under thesecircumstances, the reaction conditions convert the selected substituentinto another substituent that is either useful as an intermediatecompound or is a desired substituent in a target compound.

General Reaction Scheme provides an exemplary synthesis for compound 5.R¹, R², R³, R⁴, X, n and A are as defined in Formula (I).

Step (i) may be carried out as S_(N)2Ar reaction by starting fromcompound 1 as nucleophile to react with compound 2 using appropriatebase such as triethylamine (TEA) in an aprotic polar solvent (e.g., DMF)to provide compound 3. Step (ii) provides synthesis of compound 4through cyclization of 3 under Mitsunobu condition (e.g., DIAD, DEAD).Step (iii) may be carried out by reacting compound 4 withH—X—(CH₂)_(n)-A in the presence of a suitable base such as NaH ordiisopropyl ethylamine in a suitable solvent such as dimethylformamide(DMF) or dioxane to provide final compound 5.

Scheme 1 provides an exemplary synthesis for compound 1.5. n and A areas defined in Formula (I). X is as defined in Formula (I) except X isabsent. Step (i) may be carried out by reacting compound 1.1 withcompound 1.2 using appropriate reagents such as triethylamine (TEA) inan appropriate solvent such as acetonitrile under a suitable temperaturesuch as room temperature to provide compound 1.3. Step (ii) may be takenplace by reacting compound 1.3 with a suitable reagent such astriethylamine (TEA) and methanesulfonyl chloride (MsCl) at appropriatetemperature such as 0° C. to obtain compound 1.4. Step (iii) may becarried out by reacting compound 1.4 with H—X—(CH₂)_(n)-A, in thepresence of a suitable base such as NaH or diisopropyl ethylamine in asuitable solvent such as DMF or dioxane to provide O- or NH-linked finalcompound 1.5. Sonogashira coupling of compound 1.4 and HC≡C—W, followedby hydrogenation afforded carbon-linked compound 1.5. W is as define inFormula (I). Variation of reaction conditions and reagents, which isobvious to one one skilled in the art, may be applied for different—X—(CH₂)_(n)-A groups.

General Experimental Scheme 2 provides an exemplary synthesis forcompounds 2.5 and 2.9. n and A are as defined in Formula (I). Step (i)may be carried out by reacting compound 2.1 with compound 2.2 usingappropriate reagents such as triethylamine (TEA) in an appropriatesolvent such as acetonitrile under a suitable temperature such as roomtemperature followed by reduction with BH₃ in step (ii) to providecompound 2.3. Step (iii) may be taken place by reacting compound 2.3with a suitable reagent such as triethylamine (TEA) or K₂CO₃ andmethanesulfonyl chloride (MsCl) in an appropriate solvent such as THF ordioxane at an appropriate temperature such as 95° C. to provide compound2.4. Step (iv) may be proceeded by reacting compound 2.4 withH—X—(CH₂)_(n)-A in the presence of a suitable base such as NaH in asuitable solvent such as DMF at suitable temperature such as 0° C. orSonogashira coupling of compound 2.4 and HC≡C—W followed byhydrogenation to afford compound 2.5. W is as defined in Formula (I).Similarly to the synthesis of O-linked compound 2.5, compound 2.9 wasprepared starting from alcohol 2.6 and trichloropyrimidine 2.2.Variation of reaction conditions and reagents, which is obvious to oneone skilled in the art, may be applied for different —X—(CH₂)_(n)-Agroups.

Scheme 3 provides an exemplary synthesis for compounds 3.5. n and A areas defined in Formula (I). X is as defined in Formula (I) except X isabsent. Step (i) may be taken place by reacting compound 3.1 with asuitable reagent such as HCl in an appropriate solvent such as methanolat appropriate temperature such as room temperature to provide compound3.2. Similarly to the step (ii) of Scheme 1, compound 3.4 may beobtained in step (ii) by reacting compound 3.3 with a suitable reagentsuch as triethylamine (TEA) and methanesulfonyl chloride (MsCl) atappropriate temperature such as 0° C. to provide compound 3.4. Thenfinal compound 3.5 may be provided by carrying out step (iii) byreacting compound 3.4 with H—X—(CH₂)_(n)-A in the presence of a suitablebase such as NaH or diisopropyl ethylamine in a suitable solvent such asDMF or dioxane to provide compound 3.5. Sonogashira coupling of 3.4 andHC≡C—W followed by hydrogenation can provide carbon-linked compound 3.5.Variation of reaction conditions and reagents, which is obvious to oneone skilled in the art, may be applied for different —X—(CH₂)_(n)-Agroups.

General Experimental Scheme 4 provides an exemplary synthesis forcompound 4.5. A and n are as defined in Formula (I). X is as defined asFormula (I) except that X is NH, or N—C₁₋₃ alkyl. Step (i) may becarried out by reacting compound 4.1 with compound 4.2 using appropriatereagents such as triethylamine (TEA) in an appropriate solvent such asethanol under a suitable temperature such as room temperature to providecompound 4.3. Step (ii) may be taken place by reacting compound 4.3 witha suitable reagent such as paraformaldehyde and para-toluene sulfonicacidic (PTSA) in an appropriate solvent such as toluene under reflux toobtain compound 4.4. Final compound 4.5 may be prepared by starting fromcompound 4.4 by carrying out similar reactions described from 1.3 to 1.5in Scheme 1. Variation of reaction conditions and reagents, which isobvious to one one skilled in the art, may be applied for different—X—(CH₂)_(n)-A groups.

General Experimental Scheme 5 provides an exemplary synthesis forcompounds 5.5. A, X and n are as defined in Formula (I). Step (i) may becarried out by reacting compound 5.1 with compound 5.2 using appropriatereagents such as DIAD and Ph₃P in an appropriate solvent such as THFunder a suitable temperature such as room temperature, and then followedby desilylation in step (ii) to provide compound 5.3. Step (iii) may becarried out by oxidation with a Dess-Martin reagent followed bycyclization in step (iv) with 2-aminoethanol or 3-aminopropan-1-ol in anappropriate solvent such as dioxane to obtain compound 5.4. Step (v) maybe proceeded by reacting compound 5.4 with H—X—(CH₂)_(n)-A, in thepresence of a suitable base such as NaH in a suitable solvent such asDMF to afford compound 5.5. Variation of reaction conditions andreagents, which is obvious to one one skilled in the art, may be appliedfor different —X—(CH₂)_(n)-A groups.

General Experimental Scheme 6 provides an exemplary synthesis forcompounds 6.7 to 6.10, 6.12 and 6.16. R⁴, X, n and A are as defined inFormula (I). M¹, M², M³ and M⁴ are appropriate substituents on the ringformed by R¹ and R² as defined in Formula (I). Step (i) may be carriedout by reacting compound 6.1 with appropriate reagents such as LAH orLiAlD₄ in an appropriate solvent such as 2-MeTHF under a suitabletemperature such as room temperature to provide compound 6.2. Compound6.4 may be prepared by starting from 6.2 and 6.3 by carrying out similarreactions described from 1.3 to 1.4 in Scheme 1 by following similarreaction described from 1.4 to 1.5 in Scheme 1, and then removal of Bocgroup afforded compound 6.7 in step (iv). Step (v) may be taken place byreacting 6.7 with corresponding sulfonyl chloride, acid chloride or acidin the presence of a suitable base such as DIPEA in a suitable solventsuch as DCM to afford compound 6.8 or 6.9 respectively. Step (vi) may beproceeded by reacting 6.7 with alkyl bromide or methyl iodide in thepresence of a suitable base such as DIPEA or TEA in a suitable solventsuch as DCM to give compound 6.10. Removal of Boc group with TFA in DCMin step (vii) generated compound 6.11. Step (viii) described amide andsulfonyl amide formation using similar condition to step (v), thensubstitution in step (ix) afforded 6.12. Compound 6.14 was obtained bymethylation in the presence of methyl iodide and strong base LDA in step(xiii) followed by reduction of ester with LAH in step (xi).Hydrogenation of 6.14 may give compound 6.15 in step (xii). Compound6.16 may be prepared by starting from 6.15 in step (x) by carrying outsimilar reactions described from 1.1 to 1.5 in Scheme 1. Variation ofreaction conditions and reagents, which is obvious to one one skilled inthe art, may be applied for different —X—(CH₂)_(n)-A groups.

General Experimental Scheme 7 provides an exemplary synthesis forcompounds 7.7, 7.8 and 7.11. n and A are as defined in Formula (I). X isas defined in Formula (I) except X is absent. Step (i) may be carriedout by reacting compound 7.1 with compound 7.2 using appropriatereagents such as K₂CO₃ in an appropriate solvent such as ethanol under asuitable temperature such as 50° C. to provide compound 7.3. Step (ii)may be taken place by reacting compound 7.3 with iodomethane in thepresence of K₂CO₃ in DMF to give compound 7.4. Reduction following bycyclization in step (iii) may afford compound 7.5. Step (iv) may beproceeded by reacting compound 7.3 with 7.6, in the presence of asuitable base such as NaH or TEA in a suitable solvent such as DMF, toprovide compound 7.7. N-alkylation in step (v) may provide compound 7.8.N-methylation in step (vi) following by substitution in step (vii)provided compound 7.10. Variation of reaction conditions and reagents,which is obvious to one one skilled in the art, may be applied fordifferent —X—(CH₂)_(n)-A groups.

Scheme 8 provides an exemplary synthesis for compounds 8.6, and 8.7. X,n and A are as defined in Formula (I). X is as defined in Formula (I)except X is absent. Compound 8.3 may be prepared by starting fromcompound 8.1 and 8.2 in step (i) by carrying out similar reactionsdescribed from compound 1.3 to 1.4 in Scheme 1. Step (ii) may be carriedout by reacting compound 8.3 with 8.4, in the presence of a suitablebase such as NaH or K₂CO₃ in a suitable solvent such as DMF to providecompound 8.5. Oxidation of 8.5 with oxone in step (iii) may givecompounds 8.6 and 8.7. Variation of reaction conditions and reagents,which is obvious to one one skilled in the art, may be applied fordifferent —X—(CH₂)_(n)-A.

General Experimental Scheme 9 provides an exemplary synthesis forcompound 9.8. X, n and A are as defined in Formula (I). Protection of NHfollowed by ester formation may afford compound 9.2 in step (i) and(ii). Protection of secondary hydroxyl group by TBS in step (iii)following reduction with DIBAL-H in step (iv) may give compound 9.3.Deprotection of carboxybenzy (Cbz) under hydrogenation condition in step(v) may provide compound 9.4. Compound 9.6 may be prepared by startingfrom compound 9.4 and 9.5 in step (vi) by carrying out similar reactionsdescribed from 1.3 to 1.4 in Scheme 1. Substitution in step (vii)following removal of TVS group in step (viii) may provide compound 9.8.

Scheme 10 provides an exemplary synthesis for spiro-compounds 10.9. X, Aand n are as defined in Formula (I). Step (i) may be carried out byreacting carbonyl compound 10.1 with a suitably protected amine andtrimethylsilyl cyanide (TMSCN) to get compound 10.2. Hydrolysis withhydroxide in a protic solvent such as methanol can provide compound10.3. Reduction of 10.3 to 10.4 can be accomplished with a hydridereducing agent such as LAH in a polar solvent like THF or 2-MeTHF.Deprotection of the nitrogen protecting group on the amine can beaccomplished using standard conditions to provide compound 10.5.Coupling of the amino-alcohol 10.5 with trichloropyrimidine in a polarsolvent in the presence of an amine base such as triethylamine (TEA) ordiisopropylethylamine (DIPEA) provides alcohol 10.6. Cyclization to thefused choloropyrimidinone 10.7 can be accomplished by reaction with asuitable reagent such as TEA and methanesulfonyl chloride (MsCl) atappropriate temperature such as 0° C. followed by warming in thepresence of carbonate in acetonitrile. Boc protection of the amine canbe accomplished under standard conditions to provide key intermediate10.8. The final steps (viii) may be carried out by reacting compound10.8 with substituted benzyl alcohols or benzyl amines in the presenceof a suitable base such as NaH or diisopropyl ethylamine in a suitablesolvent such as DMF or dioxane to provide O- or NH-linked final compound10.9 after Boc-deprotection. Variation of reaction conditions andreagents, which is obvious to one one skilled in the art, may be appliedfor different —X—(CH₂)_(n)-A.

Scheme 11 provides an exemplary synthesis for spiro compounds 11.9. X, Aand n are as defined in Formula (I). A variation on the Strecker aminoacid synthesis during step (i) may be carried out to get compound 11.2from a suitably protected amine containing ketone. Reduction of compound11.1 to primary alcohol 11.3 can be accomplished with a hydride reducingagent such as LAH in a polar solvent like THF or 2-MeTHF. Coupling ofthe amino-alcohol 11.3 with trichloropyrimidine in a polar solvent inthe presence of an amine base such as TEA (triethylamine) or DIPEA(diisopropylethylamine) provides alcohol 11.4. Cyclization to the fusedcholoropyrimidinone 11.5 can be accomplished by reaction with a suitablereagent such as triethylamine (TEA) and methanesulfonyl chloride (MsCl)at appropriate temperature such as 0° C. followed by warming in thepresence of carbonate in acetonitrile. Boc protection of the amine canbe accomplished under standard conditions to provide key intermediate11.6. Steps vi and vii may be carried out by reacting compound 11.6 withsubstituted benzyl alcohols or benzyl amines in the presence of asuitable base such as NaH or diisopropyl ethylamine in a suitablesolvent such as dimethylformamide (DMF) or dioxane to provide O- orNH-linked compounds 11.8 after protecting group removal. The resultingamine 11.8 can be coupled with acids, acid chlorides, sulfonylchlorides, isocyanates, chloroformates and alkyl halides under standardconditions, and the boc-removed to provide final compound amides, ureas,sulfonamides, carbamates, and alkyl amines 11.9. Variation of reactionconditions and reagents, which is obvious to one one skilled in the art,may be applied for different —X—(CH₂)_(n)-A.

Scheme 12 provides an exemplary synthesis for spiro compounds 12.2. Aand n are as defined in Formula (I). N-alkylation of 10.7 may beaccomplished with a variety of alkylating agents such dialkyl sulfatesand alkyl (R¹) halides with an appropriate base such as NaH ordiisopropyl ethylamine in a suitable solvent such as dimethylformamide(DMF) or dioxane to provide chloropyrimidinone 12.1. The final step (ii)may be carried out by reacting compound 12.1 with substituted benzylalcohols or benzyl amines in the presence of a suitable base such as NaHor diisopropyl ethylamine in a suitable solvent such asdimethylformamide (DMF) or dioxane to provide O or NH-linked finalcompound 12.2. Variation of reaction conditions and reagents, which isobvious to one one skilled in the art, may be applied for different—X—(CH₂)_(n)-A.

Scheme 13 provides an exemplary synthesis for spiro compounds 13.4 wheren¹³ and m¹³ are independently 1 or 2. A and n are as defined in Formula(I). M¹³ is an appropriate substituent on the spiro-ring system.N-alkylation of compound 11.5 may be accomplished with a variety ofalkylating agents such dialkyl sulfates and R¹ alkyl halides with anappropriate base such as NaH or diisopropyl ethylamine in a suitablesolvent such as dimethylformamide (DMF) or dioxane to providechloropyrimidinone 13.1. Coupling of compound 13.1 (step ii) withsubstituted benzyl alcohols or benzyl amines in the presence of asuitable base such as NaH or diisopropyl ethylamine in a suitablesolvent such as dimethylformamide (DMF) or dioxane, provide O- orNH-linked compounds 13.2. Variation of reaction conditions and reagents,which is obvious to one one skilled in the art, may be applied fordifferent —X—(CH₂)_(n)-A. After protecting group removal (step iii), theresulting amine 13.3 may be coupled with acids, acid chlorides, sulfonylchlorides, isocyanates, chloroformates and alkyl halides under standardconditions to provide final compound amides, ureas, sulfonamides,carbamates, and alkyl amines 13.4.

The chemical names of compounds described in the present applicationfollows the principle of IUPAC nomenclature.

All temperatures are reported in degrees Celsius. All otherabbreviations are as described in the ACS Style Guide (American ChemicalSociety, Washington, D.C., 1986) unless the abbreviations arespecifically defined below.

LCMS Conditions:

1) Acidic conditions:

Mobile phase: water containing 0.05% TFA/0.05% acetonitrile

Column: Agilent SB-C18 4.6×30 mm-1.8 microns

Detection: MS and photodiode array detector (PDA)

2) Basic conditions:

Mobile phase: water containing 10 mmol NH₄HCO₃/acetonitrile

Column: XBridge™ C18 4.6×50 mm-3.5 microns

Detection: MS and photodiode array detector (PDA)

Mass Directed Autoprep Purification (MDAP) Conditions:

1) Acidic conditions:

Instrument: Waters instrument

Column: Sunfire Prep C18 column (5 um, 19×50 mm)

Mobile phase: water containing 0.05% TFA/acetonitrile.

2) Basic conditions:

Instrument: Waters instrument

Column: Xbridge Prep C18 column (5 um, 19×50 mm)

Mobile phase: water containing 0.04% ammonia/acetonitrile.

Chiral HPLC Conditions

Instrument: Gilson JX281

Column: Chiralpak IA 5 um 4.6*350 mm

Phase: MeOH:EtOH=50:50

Prep-HPCL Conditions:

Instrument: HPLC: Agilent 1200, MS: Agilent 6120

Column: Ultimate_XB_C18; column size: 4.6*50 mm

Mobile phase: water containing 0.02% NH₄AC/acetonitrile

Abbreviations and Resource Sources

The following abbreviations and resources are used herein below:

ISCO system—Teledyne ISCO(http://www.isco.com/html/seFlashChromatography.html)

r.t/rt/RT—room temperature

ACN—acetonitrile

AIBN—azobisisobutylonitrile

Aq.—aqueous

9-BBN—9-borabicyclo(3.3.1)nonane

Brine—saturated NaCl aqueous solution

CDI—1,1′-carbonyldiimidazole

CV—column volumes

DAST—diethylaminosulfur trifluoride

DIAD—diethyl azodicarboxylate

DIBAL-H—diisobutylaluminum hydride

DIEA—1,3-diisopropylcarbodiimide

DCM—dichloromethane

DIAD—diisopropyl azodicarboxylate

DIPEA—N,N-diisopropylethylamine

DMAP—4-dimethylaminopyridine

DMF—N,N-dimethylformamide

DMP—Dess-Martin periodinane

DMSO—dimethyl sulfoxide

EtOH—ethanol

EA/EtOAc—ethyl acetate

HATU—O-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate

KOAc—potassium acetate

LAH—lithium aluminium hydride

LDA—lithium diisopropylamide

FC—flash chromatography (usually conducted on silica gel column)

PTSA—P-toluenesulfonic Acid

MsCl—methanesulfonyl chloride

MTBE—methyl tertiary butyl ether

NaHMDS—sodiobis(trimethylsilyl)amine.

NBS—N-bromosuccinimide

NMP—N-methylpyrrolidone

sat.—saturated

T3P—propylphosphonic anhydride

TBAF—tetra-n-butylammonium fluoride

TBME—tert-butyl methyl ether

TBSCl—tert-butyldimethylsilyl chloride

TMSCN—trimethylsilyl cyanide

TEA or Et₃N—triethylamine

TFA—trifluoro acetic acid

THF—tetrahydrofuran

PE—petroleum ether

EXAMPLES

The following synthetic processes and examples are provided to morespecifically illustrate the invention. These examples are not intendedto limit the scope of the invention, but rather to provide guidance tothe skilled artisan to prepare and use the compounds, compositions, andmethods of the invention. While particular embodiments of the inventionare described, the skilled artisan will appreciate that various changesand modifications can be made without departing from the spirit andscope of the invention.

In general, the compounds of the present invention may be prepared bystandard techniques known in the art and by known processes analogousthereto. General methods for preparing compounds of the presentinvention are set forth below. All starting material and reagentsdescribed in the below general experimental schemes are commerciallyavailable.

In the procedures that follow, after each starting material, referenceto an intermediate is sometimes provided. This is provided merely forassistance to the skilled chemist. The starting material may notnecessarily have been prepared from the batch referred to.

D1 (1-(2,6-Dichloropyrimidin-4-yl)piperidin-2-yl)methanol

To a solution of 2,4,6-trichloropyrimidine (7.96 g, 43.4 mmol) inacetonitrile (50 mL) was added TEA (18.2 mL, 130 mmol) at 0° C. After 5min at room temperature, a solution of piperidin-2-ylmethanol (5.00 g,43.4 mmol) in DMF (5 mL) was added. The reaction was stirred at roomtemperature for 1 h and the mixture was then filtered and concentrated.The crude was purified via chromatography on silica gel (200-300 mesh,petroleum ether/ethyl acetate: 8/1 to 3/1) to give the title product asa white solid.

LC-MS (ESI): m/z 262[M+H]⁺; 1.59 min (ret time)

D2 4-Chloro-6-(2-(hydroxymethyl)piperidin-1-yl)pyrimidin-2(1H)-one

A mixture of (1-(2,6-dichloropyrimidin-4-yl)piperidin-2-yl)methanol(3.00 g, 11.4 mmol), LiOH (0.822 g, 34.3 mmol) and H₂O₂ (2.338 mL, 22.89mmol) in water (10 mL) was stirred overnight at 45° C. After cooled toroom temperature, the mixture was concentrated and the crude waspurified via Biotage system with inverse phase to give the titleproduct.

LC-MS (ESI): m/z 244 [M+H]⁺; 1.15 min (ret time)

D33-Chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

To a mixture of4-chloro-6-(2-(hydroxymethyl)piperidin-1-yl)pyrimidin-2(1H)-one D2 (1.00g, 4.10 mmol) and Et₃N (1.716 mL, 12.31 mmol) in THF (20 mL) was addeddropwise MsCl (0.640 mL, 8.21 mmol). The reaction mixture was stirredfor 2 hrs. The mixture was then concentrated and the crude was purifiedby HPLC to give the title product.

LC-MS (ESI): m/z 226 [M+H]⁺; 0.94 min (ret time)

¹H NMR (400 MHz, DMSO-d₆): δ 5.96 (s, 1H), 4.18-4.03 (m, 1H), 3.93 (d,J=7.3 Hz, 1H), 3.79 (d, J=12.3 Hz, 1H), 3.56 (dd, J=11.5, 7.4 Hz, 1H),3.01 (dd, J=17.3, 7.8 Hz, 1H), 1.92-1.73 (m, 2H), 1.66 (d, J=11.3 Hz,1H), 1.53-1.30 (m, 3H).

D4 (S)-1-(2,6-dichloropyrimidin-4-yl)piperidine-2-carboxylic Acid

To a solution of 2,4,6-trichloropyrimidine (14.20 g, 77.00 mmol) inacetonitrile (60 mL) was added (S)-piperidine-2-carboxylic acid (10 g,77 mmol), followed by K₂CO₃ (21.40 g, 155.0 mmol). The reaction wasstirred overnight at room temperature and then acidified with 2 M HClsolution to pH=4. The mixture was extracted with ethyl acetate twice andcombined organic parts were dried over Na₂SO₄, filtered and concentratedto give the residue as yellow oil. The crude was used into next stepwithout purification.

D5 (S)-(1-(2,6-dichloropyrimidin-4-yl)piperidin-2-yl)methanol

To a solution of(S)-1-(2,6-dichloropyrimidin-4-yl)piperidine-2-carboxylic acid (16.0 g,57.9 mmol) in dry tetrahydrofuran (THF) (160 mL) at 0° C. under N₂ wasadded slowly LiAlH₄ (8.80 g, 232 mmol). The reaction was stirred at roomtemperature for 3 hrs. The mixture was then quenched with water,filtered and the filtrate was concentrated to give the crude as brownoil, which was used into next step without purification.

LCMS (ESI): m/z 262, 264 [M+H]⁺; 2.72 min (ret time)

D6 (S)-6-chloro-4-(2-(hydroxymethyl)piperidin-1-yl)pyrimidin-2(1H)-one

To a mixture of(S)-(1-(2,6-dichloropyrimidin-4-yl)piperidin-2-yl)methanol (14.0 g, 53.4mmol) and lithium hydroxide one hydrate (6.72 g, 160 mmol) in water (96mL) was added at room temperature to H₂O₂ (33% w/w aqueous solution,10.9 mL, 106 mmol). The reaction mixture was stirred at 45° C. for 3 hrsand then quenched with Na₂S₂O₃ solution. Purification via reverse phasechromatography (water/acetonitrile, 0.05% TFA in water) afforded thetitle product as yellow oil.

LCMS (ESI): m/z 244 [M+H]⁺; 1.89 min (ret time)

D7(S)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

To a solution of(S)-6-chloro-4-(2-(hydroxymethyl)piperidin-1-yl)pyrimidin-2(1H)-one(1.10 g, 4.51 mmol) in dry tetrahydrofuran (THF) (20 mL) at roomtemperature was added Et₃N (1.89 mL, 13.5 mmol), followed by dropwiseMsCl (0.704 mL, 9.03 mmol). The reaction mixture was stirred at roomtemperature for 2 hrs. Purification via reverse phase chromatography(water/acetonitrile, 0.05% TFA in water) then MDAP afforded the titleproduct as a brown solid.

LCMS (ESI): m/z 226 [M+H]⁺; 1.34 min (ret time)

D8 (R)-1-(2,6-dichloropyrimidin-4-yl)piperidine-2-carboxylic Acid

The title compound was prepared by a procedure similar to that describedfor D4 starting from 2,4,6-trichloropyrimidine,(R)-piperidine-2-carboxylic acid and K₂CO₃.

LCMS (ESI): m/z 276 [M+H]⁺; 2.74 min (ret time)

D9 (R)-(1-(2,6-dichloropyrimidin-4-yl)piperidin-2-yl)methanol

The title compound was prepared by a procedure similar to that describedfor D5 starting from(R)-1-(2,6-dichloropyrimidin-4-yl)piperidine-2-carboxylic acid andLiAlH₄.

LCMS (ESI): m/z 262 [M+H]⁺; 2.71 min (ret time)

D10 (R)-6-chloro-4-(2-(hydroxymethyl)piperidin-1-yl)pyrimidin-2(1H)-one

The title compound was prepared by a procedure similar to that describedfor D6 starting from(R)-(1-(2,6-dichloropyrimidin-4-yl)piperidin-2-yl)methanol, lithiumhydroxide one hydrate and H₂O₂.

LCMS (ESI): m/z 244 [M+H]⁺; 1.44 min (ret time)

D11(R)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor D7 starting from(R)-6-chloro-4-(2-(hydroxymethyl)piperidin-1-yl)pyrimidin-2(1H)-one,Et₃N and MsCl.

LCMS (ESI): m/z 226 [M+H]⁺; 1.39 min (ret time)

D12 (1-(2,6-Dichloropyrimidin-4-yl)pyrrolidin-2-yl)methanol

To the solution of 2, 4, 6-trichloropyrimidine (2.176 g, 11.86 mmol) andtriethylamine (2.76 mL, 19.77 mmol) in acetonitrile (25 mL) was addeddropwise pyrrolidin-2-ylmethanol (1.0 g, 9.89 mmol) in acetonitrile (5mL) at 0° C. The mixture was stirred for 2 hrs at room temperature andcollected the solution by filtration, concentrated in vacuum and theresidue was purified via silica flash column. After removing solvent, apale solid of (1-(2, 6-dichloropyrimidin-4-yl) pyrrolidin-2-yl) methanol(1.4 g, 5.64 mmol, 57.1% yield) was afforded.

LC-MS (ESI): m/z 248 [M+H]⁺; 2.42 min (ret time).

D133-Chloro-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

To the solution of(1-(2,6-dichloropyrimidin-4-yl)pyrrolidin-2-yl)methanol (300 mg, 1.209mmol) and triethylamine (0.506 mL, 3.63 mmol) in tetrahydrofuran (15 mL)was added dropwise methanesulfonyl chloride (0.141 mL, 1.814 mmol) intetrahydrofuran (5 mL) at 0° C. and the mixture was stirred further 10min at 0° C. The result mixture was concentrated in vacuum and theresidue was added acetonitrile (20.00 mL) and potassium carbonate (836mg, 6.05 mmol). The suspension was refluxed for 4 hrs and filtrated invacuum, the filtrate was concentrated in vacuum afforded crude productof3-chloro-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one(256 mg, 1.209 mmol, 100% yield).

LC-MS (ESI): m/z 212 [M+H]⁺; 1.33 min (ret time).

D14 (R)-(1-(2, 6-dichloropyrimidin-4-yl) pyrrolidin-2-yl) methanol

The title compound was prepared by a procedure similar to that describedfor D12 starting from D-prolinol and 2, 4, 6-trichloropyrimidine.

LC-MS (ESI): m/z 248 [M+H]⁺; 2.43 min (ret time).

An exemplary synthesis is provided below: To the solution of 2, 4,6-trichloropyrimidine (3.26 g, 17.80 mmol) and triethylamine (4.13 mL,29.7 mmol) in acetonitrile (25 mL) was added dropwise D-prolinol (1.456mL, 14.83 mmol) in acetonitrile (5 mL) at 0° C. The mixture was stirredfor 2 hours at room temperature and collected the solution byfiltration, concentrated in vacuum and the residue was purified viasilica flash column. After removing solvent, a pale solid of (R)-(1-(2,6-dichloropyrimidin-4-yl) pyrrolidin-2-yl) methanol (2.5 g, 10.08 mmol,67.9% yield) was afforded.

LC-MS (ESI): m/z 248 [M+H]⁺; 2.43 min (ret time).

D15(R)-3-chloro-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor D13 starting from (R)-(1-(2, 6-dichloropyrimidin-4-yl)pyrrolidin-2-yl) methanol.

An exemplary synthesis is provided below: to the solution of (R)-(1-(2,6-dichloropyrimidin-4-yl) pyrrolidin-2-yl) methanol (1.95 g, 7.86 mmol)and triethylamine (3.29 mL, 23.58 mmol) in tetrahydrofuran (15 mL) wasadded dropwise methanesulfonyl chloride (0.919 mL, 11.79 mmol) intetrahydrofuran (5 mL) at 0° C. and the mixture was stirred for 10 minat 0° C. The result mixture was concentrated in vacuum and acetonitrile(20.00 mL) and potassium carbonate (3.26 g, 23.58 mmol) was added to theresidue. The suspension was refluxed for 4 h and filtrated in vacuum.The filtrate was concentrated in vacuum to afford the title compound(1.663 mg, 7.86 mmol, 100% yield).

LC-MS (ESI): m/z 212 [M+H]⁺; 1.33 min (ret time).

D16 (S)-(1-(2, 6-dichloropyrimidin-4-yl) pyrrolidin-2-yl) methanol

The title compound was prepared by a procedure similar to that describedfor (1-(2,6-dichloropyrimidin-4-yl)pyrrolidin-2-yl)methanol startingfrom L-prolinol and 2, 4, 6-trichloropyrimidine.

LC-MS (ESI): m/z 248 [M+H]⁺; 2.42 min (ret time).

An exemplary process is provided: To the solution of 2, 4,6-trichloropyrimidine (3.26 g, 17.80 mmol) and triethylamine (4.13 mL,29.7 mmol) in acetonitrile (25 mL) was added dropwise L-prolinol (1.456mL, 14.83 mmol) in acetonitrile (5 mL) at 0° C. The mixture was stirredfor 2 hrs at room temperature and collected the solution by filtration,concentrated in vacuum and the residue was purified via silica flashcolumn. The title compound was afforded (2.5 g, 10.08 mmol, 67.9% yield)as a pale solid.

LC-MS (ESI): m/z 248 [M+H]⁺; 2.43 min (ret time).

D17(S)-3-chloro-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor D13 starting from (S)-(1-(2, 6-dichloropyrimidin-4-yl)pyrrolidin-2-yl) methanol.

An exemplary process is provided: To the solution of (S)-(1-(2,6-dichloropyrimidin-4-yl) pyrrolidin-2-yl) methanol (400 mg, 1.612 mmol)and triethylamine (0.674 mL, 4.84 mmol) in tetrahydrofuran (15 mL) wasadded dropwise methanesulfonyl chloride (0.188 mL, 2.418 mmol) intetrahydrofuran (5 mL) at 0° C. and the mixture was stirred for 10 minat 0° C. The resulting mixture was concentrated in vacuum and theresidue was added acetonitrile (20.00 mL) and potassium carbonate (668mg, 4.84 mmol). The suspension was refluxed for 4 h and filtrated invacuum. The filtrate was concentrated in vacuum to afford the titlecompound (341 mg, 1.612 mmol, 100% yield).

D18 (4-(2,6-Dichloropyrimidin-4-yl)morpholin-3-yl)methanol

The title compound was prepared by a procedure similar to that describedfor D12 starting from morpholin-3-ylmethanol and 2, 4,6-trichloropyrimidine.

LC-MS (ESI): m/z 265 [M+H]⁺; 2.13 min (ret time).

D197-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor D13 starting from (4-(2, 6-dichloropyrimidin-4-yl) morpholin-3-yl)methanol.

D20 (S)-morpholin-3-ylmethanol Hydrochloride

To a solution of (S)-tert-butyl3-(hydroxymethyl)morpholine-4-carboxylate (10.20 g, 47.0 mmol) in MeOH(60 mL) was added dropwise HCl/MeOH (4M, 35.4 mL, 141 mmol) at 0° C. Thereaction mixture was stirred at room temperature overnight. Then themixture was concentrated under reduced pressure to give the titlecompound (8.50 g, 100%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 9.74 (br s, 1H), 9.34 (br s, 1H), 4.95 (s,2H), 3.88-3.84 (m, 2H), 3.69-3.56 (m, 3H), 3.23-2.98 (m, 3H).

D21 (S)-(4-(2, 6-dichloropyrimidin-4-yl) morpholin-3-yl) methanol

The title compound was prepared by a procedure similar to that describedfor D12 starting from morpholin-3-ylmethanol and(S)-morpholin-3-ylmethanol hydrochloride.

¹H NMR (300 MHz, CDCl₃): δ 6.47 (s, 1H), 4.11-3.92 (m, 6H), 3.68-3.53(m, 2H), 3.39-3.32 (m, 1H), 1.79 (t, J=5.7 Hz, 1H).

D22(S)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor D13 starting from(S)-(4-(2,6-dichloropyrimidin-4-yl)morpholin-3-yl)methanol.

LC-MS (ESI): m/z 228 [M+H]⁺; 2.26 min (ret time).

D23 (R)-morpholin-3-ylmethanol Hydrochloride

The title compound was prepared by a procedure similar to that describedfor D20 starting from (R)-tert-butyl3-(hydroxymethyl)morpholine-4-carboxylate.

¹H NMR (300 MHz, DMSO-d₆): δ 9.42 (br s, 2H), 5.42 (t, 1H), 2.71-3.934(m, 2H), 3.51-3.71 (m, 4H), 3.01-3.24 (m, 3H).

D24 (R)-(4-(2,6-dichloropyrimidin-4-yl)morpholin-3-yl)methanol

The title compound was prepared by a procedure similar to that describedfor D12 starting from morpholin-3-ylmethanol and(R)-morpholin-3-ylmethanol hydrochloride.

¹H NMR (300 MHz, CDCl₃): δ 6.47 (s, 1H), 3.91-4.35 (m, 6H), 3.53-3.68(m, 2H), 3.32-3.39 (m, 1H), 1.86 (t, 1H).

D25(R)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor D13 starting from(R)-(4-(2,6-dichloropyrimidin-4-yl)morpholin-3-yl)methanol.

LC-MS (ESI): m/z 228 [M+H]⁺; 2.53 min (ret time).

D26 (S)-1,3-oxazinane-4-carboxylic Acid

A solution of (S)-2-amino-4-hydroxybutanoic acid (15 g, 126 mmol) and37% formalin (11 mL, 149 mmol) in 2N NaOH (63 mL) was stirred at 2-10°C. overnight. 3N HCl was added to the reaction mixture to adjust the pHto 2-3. The solvent was removed by lyophilization to give the titlecompound (20 g, 100%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 10.18-9.65 (br s, 1H), 4.87 (d, J=9.3 Hz,1H), 4.44 (d, J=9.3 Hz, 1H), 4.29-4.24 (m, 1H), 4.03-3.98 (m, 1H),3.78-3.69 (m, 1H), 2.09-2.04 (m, 1H), 1.93-1.81 (m, 1H).

D27 (S)-3-(2,6-dichloropyrimidin-4-yl)-1,3-oxazinane-4-carboxylic Acid

To a mixture of crude (S)-1,3-oxazinane-4-carboxylic acid (7.5 g, 45mmol) in EtOH (100 mL) was added TEA (11.4 g, 113 mmol) and2,4,6-trichloropyrimidine (7.0 g, 38 mmol), the reaction mixture wasstirred overnight at room temperature. Then the reaction mixture wasfiltered and the filtrate was concentrated and the residue was purifiedby chromatography on gel silica (DCM/MeOH=15/1) to give the titlecompound (4 g, 33%) as a yellow oil. The crude compound was used in thenext step without further purification.

D28 (S)-(3-(2,6-dichloropyrimidin-4-yl)-1,3-oxazinan-4-yl)methanol

To a solution of crude(S)-3-(2,6-dichloropyrimidin-4-yl)-1,3-oxazinane-4-carboxylic acid (D27)(4.0 g, 14 mmol) in THF (50 mL) was added BH₃-THF (1M in hexane, 28 mL,28 mmol) dropwise under ice bath. After the addition, the reactionmixture was stirred at room temperature for 5 hrs. The reaction wasquenched with MeOH (5 mL) and concentrated. The residue was purified bycolumn chromatography on gel silica (PE/EA=2/1) to give the titlecompound (620 mg, 17%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 5.78 (s, 1H), 4.97 (d, J=9.3 Hz, 1H), 4.64(d, J=9.3 Hz, 1H), 4.51-4.20 (m, 3H), 4.06-3.97 (m, 1H), 3.78-3.69 (m,1H), 2.06-2.01 (m, 1H), 1.86-1.71 (m, 1H).

D29 (S)-(3-(2,6-dichloropyrimidin-4-yl)-1,3-oxazinan-4-yl)methylMethanesulfonate

To a solution of(S)-(3-(2,6-dichloropyrimidin-4-yl)-1,3-oxazinan-4-yl)methanol (600 mg,2.28 mmol) in DCM (10 mL) was added MsCl (273 mg, 2.40 mmol) and TEA(460 mg, 4.56 mmol) at 0° C. After stirring at 0° C. for 20 min, H₂O (10mL) was added and and the mixture was extracted with DCM. The organiclayer was washed with brine and dried over Na₂SO₄, filtered andconcentrated to give the title compound (700 mg, 90%) which was used thein next step without further purification.

D30(S)-3-chloro-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one

To a solution of(S)-(3-(2,6-dichloropyrimidin-4-yl)-1,3-oxazinan-4-yl)methylmethanesulfonate (700 mg, 2.05 mmol) in dioxane (4 mL) and H₂O (2 mL)was added K₂CO₃ (700 mg, 5.13 mmol). The reaction mixture was stirred at95° C. for 2 hrs. After cooled to room temperature, H₂O (10 mL) wasadded and the reaction mixture extracted with DCM. The organic layer waswashed with brine and dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by column chromatography on gel silica(DCM/MeOH=50/1) to give the title compound (250 mg, 54%) as a whitesolid.

¹H NMR (300 MHz, CDCl₃): δ 5.73 (s, 1H), 5.04 (d, J=11.4 Hz, 1H), 4.65(d, J=11.1 Hz, 1H), 4.25-4.09 (m, 3H), 3.99-3.94 (m, 1H), 3.83-3.74 (m,1H), 2.02-1.97 (m, 1H), 1.75-1.70 (m, 1H).

D31 (R)-1,3-oxazinane-4-carboxylic Acid

A solution of (R)-2-amino-4-hydroxybutanoic acid (15 g, 126 mmol) and37% formaldehyde (11 mL, 149 mmol) in 2N NaOH (63 mL) was stirred at2-10° C. overnight. 3N HCl was added to the reaction mixture to adjustthe pH=2-3. The solvent was removed under lyophilization to give thetitle compound (16 g, 92%) as a white solid. The residue was used the innext step without further purification.

¹H NMR (300 MHz, DMSO-d₆): δ 10.18-9.65 (br s, 1H), 4.86 (d, J=9.0 Hz,1H), 4.44 (d, J=9.0 Hz, 1H), 4.28-4.23 (m, 1H), 4.02-3.97 (m, 1H),3.78-3.70 (m, 1H), 2.09-2.04 (m, 1H), 1.93-1.83 (m, 1H).

D32 (R)-3-(2,6-dichloropyrimidin-4-yl)-1,3-oxazinane-4-carboxylic Acid

To a mixture of crude (R)-1,3-oxazinane-4-carboxylic acid (8.4 g, 50mmol) in EtOH (120 mL) was added TEA (12.6 g, 125 mmol) and2,4,6-trichloropyrimidine (10 g, 54 mmol). The reaction mixture wasstirred overnight at room temperature. Then the reaction mixture wasfiltered and the filtrate was concentrated. The residue was purified bycolumn chromatography on gel silica (DCM/MeOH=15/1) to give the titlecompound (6.0 g, 40%) as yellow oil. The crude compound was used in thenext step without further purification.

D33 (R)-(3-(2,6-dichloropyrimidin-4-yl)-1,3-oxazinan-4-yl)methanol

To a solution of crude(R)-3-(2,6-dichloropyrimidin-4-yl)-1,3-oxazinane-4-carboxylic acid (4.5g, 16 mmol) in THF (50 mL) was added BH₃-THF (1M in hexane, 32 mL, 32mmol) dropwise under ice bath. After the addition, the reaction mixturewas stirred at room temperature for 5 hrs. The reaction was quenchedwith MeOH (5 mL) and concentrated. The residue was purified by columnchromatography on gel silica (PE/EA=2/1) to give the title compound (800mg, 19%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 5.78 (s, 1H), 4.97 (d, J=9.3 Hz, 1H), 4.64(d, J=9.3 Hz, 1H), 4.51-4.20 (m, 3H), 4.06-3.97 (m, 1H), 3.78-3.69 (m,1H), 2.06-2.01 (m, 1H), 1.86-1.71 (m, 1H).

D34 (R)-(3-(2,6-dichloropyrimidin-4-yl)-1,3-oxazinan-4-yl)methylMethanesulfonate

To a solution of(R)-(3-(2,6-dichloropyrimidin-4-yl)-1,3-oxazinan-4-yl)methanol (800 mg,3.04 mmol) in DCM (10 mL) was added MsCl (362 mg, 3.20 mmol) and TEA(614 mg, 6.08 mmol) at 0° C. After stirring at 0° C. for 20 min, H₂O (10mL) was added and the reaction mixture was extracted with DCM. Theorganic layer was washed with brine and dried over Na₂SO₄, filtered andconcentrated to give the title compound (600 mg, 75%) which was used inthe next step without further purification.

D35(R)-3-chloro-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one

To a solution of(R)-(3-(2,6-dichloropyrimidin-4-yl)-1,3-oxazinan-4-yl)methylmethanesulfonate (600 mg, 1.76 mmol) in dioxane (4 mL) and H₂O (2 mL)was added K₂CO₃ (728 mg, 5.28 mmol), the reaction mixture was stirred at95° C. for 2 hrs. After cooled to room temperature, H₂O (10 mL) wasadded and the reaction mixture was extracted with DCM. The organic layerwas washed with brine and dried over Na₂SO₄, filtered and concentrated.The residue was purified by column chromatography on gel silica(DCM/MeOH=50/1) to give the title compound (200 mg, 46%) as a whitesolid.

¹H NMR (300 MHz, CDCl₃): δ 5.73 (s, 1H), 5.04 (d, J=11.4 Hz, 1H), 4.65(d, J=11.1 Hz, 1H), 4.25-4.09 (m, 3H), 3.99-3.94 (m, 1H), 3.83-3.74 (m,1H), 2.02-1.97 (m, 1H), 1.75-1.70 (m, 1H).

D36 2-((2,6-Dichloropyrimidin-4-yl)amino)propane-1,3-diol

To a solution of 2,4,6-trichloropyrimidine (12.49 g, 68.0 mmol) in THF(120 mL) was added Et₃N (10.30 g, 102.0 mmol) and2-aminopropane-1,3-diol (6.20 g, 68.0 mmol) in EtOH (30 mL) was addeddropwise at 0° C., then stirred at room temperature overnight. Thereaction mixture was concentrated and the residue was purified by columnchromatography on silica gel eluting with DCM/MeOH (5:1) to give thetitle compound (7.53 g, 47%) as a white solid.

¹H NMR (300 MHz, CD₃OD): δ 6.50 (s, 1H), 4.20-4.23 (m, 1H), 3.72-3.62(m, 4H).

D37 (3-(2,6-Dichloropyrimidin-4-yl)oxazolidin-4-yl)methanol

A mixture of 2-((2,6-dichloropyrimidin-4-yl)amino)propane-1,3-diol (7.51g, 31.6 mmol), paraformaldehyde (947 mg, 31.6 mmol) and PTSA (300 mg,1.6 mmol) in toluene (150 mL) was heated to reflux for 2 hours. Thereaction mixture was cooled to room temperature and concentrated, theresidue was purified by column chromatography on silica gel eluting withDCM/MeOH (100:1) to give the title compound (2.86 g, 36%) as a whitesolid.

¹H NMR (300 MHz, CDCl₃): δ 6.29 (s, 1H), 5.04-4.99 (m, 2H), 4.13-4.11(m, 3H), 3.81-3.78 (m, 2H).

D38 (3-(2,6-Dichloropyrimidin-4-yl)oxazolidin-4-yl)methylMethanesulfonate

To a solution of (3-(2,6-dichloropyrimidin-4-yl)oxazolidin-4-yl)methanol(2.86 g, 11.4 mmol) and Et₃N (2.31 g, 22.9 mmol) in DCM (50 mL) wasadded dropwise methanesulfonyl chloride (1.38 g, 12.0 mmol) at 0° C. andthe reaction mixture was stirred at room temperature for 0.5 h. Thereaction was quenched with water (100 mL) and extracted with DCM (2×50mL). The organic layer was combined, washed with brine (50 mL), driedover Na₂SO₄, filtered and concentrated to give the title compound (3.46g, 92%) as a yellow power which was used directly for next step.

D396-Chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

To a solution of (3-(2,6-dichloropyrimidin-4-yl)oxazolidin-4-yl)methylmethanesulfonate (3.46, 10.5 mmol) in dioxane/H₂O (1:1, 40 mL) was addedK₂CO₃ (4.37 g, 31.5 mmol) at room temperature. The reaction mixture wasstirred at 95° C. for 7 hours. After cooled to room temperature, themixture was diluted with water (20 mL), and extracted with DCM (2×100mL). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel eluting with DCM/MeOH (50:1) to give thetitle compound (908 mg, 36%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 5.85 (s, 1H), 5.00-4.99 (m, 1H), 4.63-4.61(m, 1H), 4.37-4.12 (m, 4H), 3.59-3.53 (m, 1H).

D40(R)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-oneD41(S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The racemic6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(5.03 g, 23.6 mmol) was separated by chiral HPLC to give R-isomer (1.75g, 35%) as a white solid and S-isomer (2.07 g, 41%) as a white solid.(Chiral Analysis Method: Column: chiralpak AYH (0.46 cm I.D×15 cm L);Wavelength: 230 nm; Mobile phase: hexane/methanol/DEA=70/30/0.2 (V/V/V);T=40° C.; Flow rate: 0.899 mL/min; Injection volume: 8 μL; Run time: 10min.)

D40: Rt=5.85 min (identical with LT111530-168, chiral synthesis),Optical purity 99.5% (230 nm)

¹H NMR (300 MHz, CDCl₃): δ 5.86 (s, 1H), 5.01-4.99 (m, 1H), 4.63-4.61(m, 1H), 4.34-4.12 (m, 4H), 3.59-3.54 (m, 1H).

D41: Rt=7.18 min, Optical purity 99.3% (230 nm)

¹H NMR (300 MHz, CDCl₃): δ 5.86 (s, 1H), 5.01-4.99 (m, 1H), 4.63-4.61(m, 1H), 4.35-4.12 (m, 4H), 3.59-3.56 (m, 1H).

D421-(2-((Tert-butyldimethylsilyl)oxy)ethyl)-6-chloropyrimidine-2,4(1H,3H)-dione

To a solution of 6-chloropyrimidine-2,4(1H,3H)-dione (100.0 g, 0.680mol), 2-((tert-butyldimethylsilyl)oxy)ethanol (143.6 g, 0.816 mol) andPh₃P (267.2 g, 1.02 mol) in dry THF (2000 mL) was added DIAD (206.0 g,1.02 mol) in dry THF (500 mL) dropwise under N₂ at room temperature andthe mixture was stirred overnight. The mixture was concentrated invacuo. The residue was triturated with PE/EA (1:1, 500 mL), filtered andconcentrated. The residue was purified by column chromatography onsilica gel (PE/EA=5/1) to give the title compound (125.0 g, 60%) as awhite solid.

¹H NMR (300 MHz, CDCl₃): δ 9.93 (br s, 1H), 5.87 (s, 1H), 4.19 (t, J=5.7Hz 2H), 3.83 (t, J=5.7 Hz 2H), 0.84 (s, 9H), 0.02 (s, 6H).

D43 6-Chloro-1-(2-hydroxyethyl)pyrimidine-2,4(1H,3H)-dione

To a solution of1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-chloropyrimidine-2,4(1H,3H)-dione(125.0 g, 0.410 mol) in dry MeOH (1200 mL) was added concentrated. HCl(12 N, 3.0 mL) at room temperature and the reaction mixture was stirredfor 2 hrs, concentrated to remove MeOH. The residue was triturated withhexane (800 mL) to give the title compound (75.0 g, 96%) as a whitesolid.

¹H NMR (300 MHz, DMSO-d₆): δ 11.57 (s, 1H), 5.90 (s, 1H), 4.96 (t, J=6.3Hz 1H), 3.98 (t, J=6.0 Hz 2H), 3.56 (t, J=5.7 Hz 2H).

D44 2-(6-Chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetaldehyde

To a solution of 6-chloro-1-(2-hydroxyethyl)pyrimidine-2,4(1H,3H)-dione(75.0 g, 0.395 mol) in dry DCM (2000 mL) was added Dess-Martinperiodinane (249 g, 0.593 mol) in one portion at room temperature. Thenthe mixture was stirred at 35° C. for 2 hrs and concentrated in vacuo at35° C. The residue was purified by column chromatography on silica gel(PE/EA=5/1 to 2/1) to give the title compound (35.0 g, 47%) as a whitesolid.

¹H NMR (300 MHz, DMSO-d₆): δ 11.56 (s, 1H), 9.58 (s, 1H), 6.00 s 1H),4.93 (s, 2H).

D4510,10a-Dihydro-2H-oxazolo[3′,2′:3,4]imidazo[1,2-c]pyrimidine-6,8(3H,7H)-dione

To a solution of 2-aminoethanol (2.64 g, 42.6 mmol) in dioxane (100 mL)was added 2-(6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetaldehyde (8.00 g, 42.6 mmol) in dioxane (100 mL) dropwise at80° C. After stirred for 1 h, the mixture was concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(DCM/MeOH=40/1) to give the title compound (3.0 g, 36%) as a whitesolid.

¹H NMR (300 MHz, DMSO-d₆): δ 10.75 (br s, 1H), 5.12 (d, J=4.2 Hz 1H),5.03 (s, 1H), 4.07-3.79 (m, 4H), 3.64-3.41 (m, 2H).

D463,4,11,11a-Tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-b][1,3]oxazine-7,9(2H,8H)-dione

To a solution of 3-aminopropan-1-ol (2.0 g, 26.6 mmol) in dioxane (200mL) was added2-(6-chloro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetaldehyde (5.0 g,26.6 mmol) in dioxane (100 mL) dropwise at 80° C. and the mixture wasthen stirred for further 1 h. The mixture was concentrated in vacuo. Theresidue was purified by column chromatography on silica gel eluted withDCM/MeOH (40:1) to give the title compound (2.1 g, 38%) as a whitesolid.

¹H NMR (300 MHz, DMSO-d₆): δ 10.52 (br s, 1H), 5.26 (d, J=5.1 Hz 1H),4.90 (s, 1H), 3.98-3.62 (m, 6H), 3.49-3.34 (m, 2H).

D47 (4-Methylpiperazin-2-yl)methanol

To a mixture of tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate(1.0 g, 4.6 mmol) in THF (20 mL) was added LiAH₄ (440 mg, 11.6 mmol) atroom temperature. The mixture was heated to reflux for 2 hours, thencooled to 0° C. and quenched with MeOH (10 mL) and saturated potassiumsodium tartrate (10 mL). The mixture was filtrated and the filtrate wasevaporated to afford the title compound (600 mg, yield 100%) as yellowoil.

¹H NMR (300 MHz, CDCl₃): δ 3.62-3.57 (m, 1H), 3.50-3.45 (m, 1H),3.04-2.99 (m, 1H), 2.95-2.85 (m, 2H), 2.73-2.60 (m, 2H), 2.29 (s, 3H),2.07-1.99 (m, 1H), 1.86-1.79 (m, 1H).

D48 (1-(2,6-Dichloropyrimidin-4-yl)-4-methylpiperazin-2-yl)methanol

A solution of 2,4,6-trichloropyrimidine (847 mg, 4.6 mmol),(4-methylpiperazin-2-yl)methanol (600 mg, 4.6 mmol) and TEA (1.40 g,13.8 mmol) in EtOH (15 mL) was stirred at room temperature for 6 hours,concentrated and purified by flash chromatography on silica gel(DCM/MeOH=50/1) to give the title compounds (460 mg, yield 37%) as awhite solid.

¹H NMR (300 MHz, CDCl₃): δ 6.56 (s, 0.22H), 6.44 (s, 0.71H), 4.72-4.71(m, 0.39H), 4.57-4.50 (m, 0.38H), 4.05-3.99 (m, 1H), 3.95-3.88 (m, 1H),3.65-3.54 (m, 1H), 3.12-3.07 (m, 1H), 2.97-2.88 (m, 1H), 2.84-2.71 (m,1H), 2.37-2.35 (m, 1H), 2.32-2.31 (m, 3H), 2.19-2.08 (m, 1H).

D497-Chloro-2-methyl-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

To a solution of(1-(2,6-dichloropyrimidin-4-yl)-4-methylpiperazin-2-yl)methanol (460 mg,1.67 mmol) and TEA (337 mg, 3.33 mmol) in DCM (10 mL) was added MsCl(229 mg, 2.00 mmol) at 0° C. The mixture was stirred at room temperaturefor 1 hour and concentrated. The residue was treated with K₂CO₃ (460 mg,3.33 mmol), dioxane (20 mL) and H₂O (4 mL) and the resulting mixture washeated to 70° C. for 3 hours, and then concentrated and purified byprep-TLC (DCM/MeOH=10/1) to give the title compound (100 mg) as a yellowsolid.

¹H NMR (300 MHz, DMSO-d₆): δ 6.01 (s, 1H), 4.10-4.02 (m, 2H), 3.81-3.76(m, 1H), 3.66-3.55 (m, 1H), 3.21-3.11 (m, 1H), 2.91-2.87 (m, 1H,2.76-2.71 (m, 1H), 2.21 (m, 3H), 1.99-1.90 (m, 2H).

D50 3-Benzyl 1-tert-butyl 4-benzyl-3-methylpiperazine-1,3-dicarboxylate

3-Benzyl 1-tert-butyl 4-benzylpiperazine-1,3-dicarboxylate (2 g, 4.87mmol) was dried in a 250 mL round bottom flask under high vacuum priorto use. THF (50 mL) was added under argon, and the vessel cooled to 0°C. LDA (˜1.5 M in THF) (3.4 mL, 5.10 mmol) was added dropwise. Thereaction was stirred for 30 min at 0° C. and then quenched by additionof MeI (0.76 mL, 12.15 mmol). After stirring 15 min, the reaction wasconcentrated under reduced pressure. The crude was purified on aCombiflash silica cartridge (12 g) (0%-30% EtOAc/hexanes) to give thetitle compound (832 mg, 1.96 mmol, 40.2% yield) as tan yellow oil.

LC/MS: m/z 425.2 (M+H)⁺, 1.23 min (ret. time);

¹H NMR (400 MHz, CD₂Cl₂): δ 7.17-7.46 (m, 10H), 5.02-5.30 (m, 2H), 4.22(d, J=11.54 Hz, 1H), 3.98 (d, J=14.56 Hz, 1H), 3.69 (d, J=12.55 Hz, 1H),3.62 (d, J=14.56 Hz, 1H), 2.93-3.15 (m, 2H), 2.68-2.87 (m, 1H), 2.47 (m,1H), 1.42 (m, 12H).

D51 tert-Butyl4-benzyl-3-(hydroxymethyl)-3-methylpiperazine-1-carboxylate

A solution of 3-benzyl 1-tert-butyl4-benzyl-3-methylpiperazine-1,3-dicarboxylate (890 mg, 2.096 mmol) in2-MeTHF (15 mL) was cooled to 0° C. under argon. LAH (2.3 M, in 2-MeTHF)(1 mL, 2.3 mmol) was added slowly. The reaction was quenched by additionof saturated Na₂SO₄ (0.38 mL, [4.4 mL per gram LAH]) after 1 h stirring,filtered and the filter cake was extracted with EtOAc. The combinedorganic layer was concentrated to give the title compound (714 mg, 2.23mmol, 106% yield) as viscous yellow oil that was used without furtherpurification.

LC/MS: m/z 321.1 (M+H)⁺, 0.64 min (ret. time)

D52 tert-Butyl4-(2,6-dichloropyrimidin-4-yl)-3-(hydroxymethyl)-3-methylpiperazine-1-carboxylate

tert-Butyl 4-benzyl-3-(hydroxymethyl)-3-methylpiperazine-1-carboxylate(714 mg, 2.23 mmol) was dissolved in methanol (53 mL, in portions) andadded to a 100 mL graduated cylinder. The solution was hydrogenated onan H-Cube through a 20% Pd(OH)₂/C cartridge at 60° C., using additionalMeOH (20 mL) to ensure all of the starting material transferred throughthe H-Cube. The solution was concentrated under reduced pressure, thentransferred to a 20 mL vial using EtOH, and concentrated under a streamof nitrogen at 50° C. A stirbar was added, then ethanol (12 mL), Na₂CO₃(260 mg, 2.451 mmol), and 2,4,6-trichloropyrimidine (0.282 mL, 2.451mmol) and the reaction was stirred over the weekend (66 h). ˜80% of thestarting material remained after stirring over the weekend. The reactionwas concentrated under a stream of nitrogen at 50° C. then dissolved inDMF (10 mL). The reaction was stirred at room temperature overnight (20h) then filtered through a 0.2 μm acrodisc. The filtrate wasconcentrated, then applied to isolute using DCM and concentrated under astream of nitrogen at 50° C. The crude product was purified on aCombiflash silica cartridge (24 g) (0%-60% EtOAc/hexanes) to give thetitle compound (329 mg, 0.87 mmol, 39% yield) as a clear oil.

LC/MS: m/z 377.1 (M+H)⁺, 1.05 min (ret. time)

D53 tert-Butyl7-chloro-11a-methyl-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2(9H)-carboxylate

A solution of tert-butyl4-(2,6-dichloropyrimidin-4-yl)-3-(hydroxymethyl)-3-methylpiperazine-1-carboxylate(35 mg, 0.093 mmol) in THF (1.2 mL) was cooled to 0° C. and TEA (0.03mL, 0.215 mmol) then MsCl (0.01 mL, 0.128 mmol) as a solution in THF(0.1 mL) were added dropwise and stirred for 15 min at 0° C. Thereaction was then concentrated under a stream of nitrogen at 50° C.,resulting in a white solid. The resulting material was taken up inacetonitrile (1.2 mL). K₂CO₃ (39 mg, 0.282 mmol) was added, and theresulting suspension was heated to 80° C. for 40 min. After cooling toroom temperature, the reaction mixture was filtered, concentrated. Theresidue was partitioned between H₂O (1 mL) and CH₂Cl₂ (3 mL). The layerswere separated and the aqeuous phase was further extracted with CH₂Cl₂(2×1 mL). The combined organic phases were concentrated under a streamof nitrogen at 50° C. to give the title compound (29 mg, 0.085 mmol, 92%yield) as a mustard yellow solid. The crude material was used withoutfurther purification.

LC/MS: m/z 341.1 (M+H)⁺, 0.71 min (ret. time);

¹H NMR (400 MHz, CD₂Cl₂): δ 3.78-4.13 (m, 2H), 3.71 (s, 2H), 3.11-3.21(m, 2H), 2.68-2.99 (m, 2H), 1.28 (s, 12H).

D54 tert-Butyl 3-(dideutero(hydroxy)methyl)piperazine-1-carboxylate

A suspension of 4-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (4.5g, 19.54 mmol) in 2-methyltetrahydrofuran (2-MeTHF) (60 ml) wassonicated for 20 min, cooled to 0° C., then a solution of Lithiumaluminum deuteride (1M in THF) (24.5 ml, 24.50 mmol) was added inportions. The reaction mixture was stirred for 15 min at 0° C., thenstirred at room temperature for 20 h. The reaction was quenched withsaturated Na₂SO₄ (2.6 mL) dropwise, and stirred for an additional 15min, filtered and the filtercake was further extracted with EtOAc (6×50mL). The filtrate was dried over anhydrous Na₂SO₄, filtered andconcentrated to give the title compound (3.47 g, 15.90 mmol, 81% yield)as a red sticky solid, which was used without further purification.

LC/MS: m/z 219.0 (M+H)⁺, 0.34 min (ret. time)

D55 tert-Butyl4-(2,6-dichloropyrimidin-4-yl)-3-(dideutero(hydroxy)methyl)piperazine-1-carboxylate

The title compound was prepared by a procedure similar to that describedfor D52 starting from tert-butyl3-(hydroxymethyl)piperazine-1-carboxylate.

LC/MS: m/z 365.0 (M+H)⁺, 0.98 min (ret. time)

¹H NMR (400 MHz, CDCl₃): δ 4.16-4.47 (m, 2H), 3.99 (dd, J=11.04, 3.51Hz, 1H), 3.68 (s, 1H), 3.47 (br. s., 1H), 3.25 (d, J=2.76 Hz, 1H),2.74-2.98 (m, 2H), 1.50 (s, 9H).

D56 tert-Butyl7-chloro-11,11-dideutero-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2(9H)-carboxylate

The title compound was prepared by a procedure similar to that describedfor D53 starting from tert-butyl4-(2,6-dichloropyrimidin-4-yl)-3-(dideutero(hydroxy)methyl)piperazine-1-carboxylate.

LC/MS: m/z 329.0 (M+H)⁺, 0.67 min (ret. time)

D57 tert-Butyl4-(2,6-dichloropyrimidin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate

To a mixture of tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate(14.05 g, 65.0 mmol) and Na₂CO₃ (8.2 g, 77 mmol) was added ethanol (316ml) followed by addition of 2,4,6-trichloropyrimidine (9 ml, 78 mmol).The reaction mixture was stirred for 3 d at rt, filtered through acinter funnel, concentrated, and taken up in DCM. Then Isolute wasadded, and the heterogeneous mixture was concentrated. The residue waspurified on a Combiflash silica cartridge (330 g) (0%-70% EtOAc/hexanes)to give the title compound (7.1 g, 19.55 mmol, 30.1% yield) as anorange-white amorphous solid.

LC/MS: m/z 363.2 (M+H)⁺, 0.92 min (ret. time)

D58 tert-Butyl7-chloro-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2(9H)-carboxylate

A solution of tert-butyl4-(2,6-dichloropyrimidin-4-yl)-3-(hydroxymethyl)piperazine-1-carboxylate(7.1 g, 19.55 mmol) in THF (225 ml) was cooled to 0° C. and TEA (5.45ml, 39.1 mmol) then MsCl (1.675 ml, 21.50 mmol) as a solution in THF (25ml) were added dropwise, stirred for 15 min at 0° C. The reactionmixture was then concentrated, and the residue was taken up inacetonitrile (250 ml). K₂CO₃ (8.10 g, 58.6 mmol) was added, and theresulted suspension was heated to 80° C. for 38 min. After cooling tort, the reaction mixture was filtered and the filtrate was concentrated.The residue was partitioned between H₂O (100 mL) and CHCl₃ (100 mL). Thelayers were separated and the aqeuous phase was further extracted withCHCl₃ (3×50 mL). The organic phases were combined and concentrated underreduced pressure to give the title compound (6.23 g, 19.06 mmol, 98%yield) as an amorphous brown/red solid. The crude material was usedwithout further purification.

LC/MS: m/z 327.0 (M+H)⁺, 0.68 min (ret. time);

¹H NMR (400 MHz, CDCl₃): δ 5.49 (s, 1H), 3.95-4.42 (m, 4H), 3.69 (dd,J=12.05, 7.53 Hz, 1H), 3.48 (d, J=11.29 Hz, 1H), 3.22 (td, J=12.42, 2.76Hz, 1H), 3.08-2.78 (m, 2H), 1.45 (s, 9H).

D597-Chloro-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

To a solution of tert-butyl7-chloro-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2(9H)-carboxylate (1.84 g, 5.63 mmol) in dry dichloromethane(DCM) (6.5 mL was added TFA (6.5 mL, 84 mmol). The reaction mixture wasstirred at rt for 1.75 h, concentrated under a stream of nitrogen at 50°C., taken up in DCM/MeOH and concentrated under a stream of nitrogen at50° C., then placed under high vacuum to give the title compound (2.01g, 6.47 mmol, 115% yield) as a brown solid that was used withoutpurification.

LC/MS: m/z 226.9 (M+H)⁺, 0.1 min (ret. time)

D60 1-(2,6-Dichloropyrimidin-4-yl)-5-oxopiperazine-2-carboxylic Acid

To a suspension of 5-oxopiperazine-2-carboxylic acid (2000 mg, 13.88mmol) and sodium carbonate (2941 mg, 27.8 mmol) in ethanol (50 mL) wasadded 2,4,6-trichloropyrimidine (1.596 mL, 13.88 mmol). The reactionmixture was heated to 50° C. overnight, concentrated. Then 20 mL waterwas added, filtered and got 2.9 g1-(2,6-dichloropyrimidin-4-yl)-5-oxopiperazine-2-carboxylic acid as awhite solid (with some minor isomer).

LC/MS: m/z 290.8 (M+H)⁺, 0.55 min(ret. time)

D61 Methyl 1-(2,6-dichloropyrimidin-4-yl)-5-oxopiperazine-2-carboxylate

To a suspension of1-(2,6-dichloropyrimidin-4-yl)-5-oxopiperazine-2-carboxylic acid (2900mg, 9.96 mmol) and potassium carbonate (4131 mg, 29.9 mmol) in DMF (20mL) was added iodomethane (1.246 mL, 19.93 mmol). The reaction mixturewas stirred at rt for 30 min, and concentrated. Then water and EA wereadded, filtered to get 866 mg crude solid product. The filtrate wasseparated and extracted the aqueous layer twice with EA, concentrated.The crude product was purified via CombiFlash Rf 200 with a gradient of100% DCM to 10% MeOH in DCM to afford the title compound (940 mg) as awhite solid.

LC/MS: m/z 304.8 (M+H)⁺, 0.63 min(ret. time)

D62 4-(2,6-Dichloropyrimidin-4-yl)-5-(hydroxymethyl)piperazin-2-one

To a solution of methyl1-(2,6-dichloropyrimidin-4-yl)-5-oxopiperazine-2-carboxylate (1800 mg,5.90 mmol) in ethanol (50 mL) was added sodium tetrahydroborate (670 mg,17.70 mmol). The reaction mixture was stirred at rt overnight. Thenacetic acid (2.362 mL, 41.3 mmol) was added and stirred for 10 min,concentrated, and then EA and water were added. The water layer wasextracted twice with EA. The combined organic layers were concentratedand purification via CombiFlash Rf 200 afforded the title compound (807mg) as a white solid.

LC/MS: m/z 276.9 (M+H)⁺, 0.46 min(ret. time)

D637-Chloro-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione

To a solution of4-(2,6-dichloropyrimidin-4-yl)-5-(hydroxymethyl)piperazin-2-one (807 mg,2.91 mmol) in THF (30 mL) at 0° C. was added methanesulfonyl chloride(0.295 mL, 3.79 mmol) and triethylamine (0.807 mL, 5.82 mmol). Thereaction mixture was stirred at 0° C. for 30 min, concentrated. Theresidue was taken up in acetonitrile (30.0 mL), and then potassiumcarbonate (1207 mg, 8.74 mmol) was added. The resulted suspension washeated to 82° C. for 1 h, filtered and concentrated. The residue waspurified using CombiFlash Rf 200 to afford the title compound (450 mg)as a white solid.

LC/MS: m/z 241.0 (M+H)⁺, 0.20 min(ret. time)

D647-Chloro-2-methyl-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione

A suspension of7-chloro-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione(200 mg, 0.831 mmol) and 18-crown-6 (10.39 mg, 0.042 mmol) in THF (14mL) and DMSO (2 mL) at 0° C., was added sodium hydride (49.9 mg, 1.247mmol). The reaction mixture was stirred for 20 min at rt, then,iodomethane (0.083 mL, 1.330 mmol) was added at 0° C. The reactionmixture was stirred at rt overnight, quenched by addition of water, andconcentrated. The residue was purified using CombiFlash Rf 200 to affordthe title compound (200 mg) as a yellow solid.

LC/MS: m/z 254.9 (M+H)⁺, 0.16 min(ret. time)

D65 4-(2,6-Dichloropyrimidin-4-yl)thiomorpholin-3yl)methanol

To a mixture of the thiomorpholin-3-ylmethanol (1.23 g, 9.20 mmol, 1.0equiv) and 2,4,6-trichloropyrimidine (1.86 g, 10.12 mmol, 1.1 equiv) inEtOH (25 mL) at 0° C. was added Et₃N (1.54 mL, 1.2 equiv) dropwise. Thereaction mixture was stirred overnight, concentrated. The residue waspartitioned between 5% MeOH in DCM (100 and 50 mL) and water (30 mL) andsaturated NaHCO₃ solution (10 mL). The combined organic was dried overNa₂SO₄, filtered and concentrated to afford 3 g of the crude as a clearthick oil. This crude material was combined with the crudes from twoscout runs starting from a total of 1.00 g ofthiomorpholin-3-ylmethanol. These crude materials were adsorbed ontoIsolute. Purification was performed on a Teledyne-Isco Combiflash Rfsystem using a Redi-Sep 80 g silica gel cartridge with gradient elutionof 0% EtOAc in hexane to 70% EtOAc in hexane over a 40 min period (thefirst 5 min was holding time for 0% EtOAc in hexane, flow rate at 60mL/min, UV at 254 nm). There were three peaks eluting out. The thirdpeak was the desired product. The appropriate fractions were combinedand concentrated to give the title compound as a white foamy residue(2.87 g).

LC/MS: m/z 280/282 (M/M+2)⁺, 0.76 min (ret. time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.05 (s, 1H), 4.90 (t, J=5.65 Hz, 1H), 3.80(br. s., 2H), 2.89 (br. s., 1H), 2.71 (s, 1H), 2.74 (s, 2H), 2.62 (br.s., 1H).

D667-Chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one

To a chilled (ice bath) solution of (4-(2,6-dichloropyrimidin-4yl)thiomorpholin-3-yl)methanol (2.70 g, 9.64 mmol,1.0 equiv) in THF (70 mL) was added Et₃N (4.0 mL, 28.90 mmol, 3.0 equiv)and then a solution of MsCl (1.66 g, 14.46 mmol, 1.5 equiv) in THF (15mL) portion wise. The reaction mixture was stirred at 0° C. for 30 min,and then concentrated. The residue was taken up in 80 ml of ACN,followed by addition of K₂CO₃ (4.00 g, 28.90 mmol, 3.0 equiv). Themixture was heated at 85° C. for 1.5 h. The mixture was cooled to rt,and filtered. The filtrate was concentrated to give a light brownishresidue. This residue was partitioned between 5% MeOH in DCM (100 mL, 50mL, 2×30 mL) and brine (15 mL) and 5 mL of saturated NaHCO₃. The middleemulsion was filtered through celite to give a clear phase separation.The combined organic was dried over Na₂SO₄, filtered, and concentratedto give a brownish residue (3.15 g). This residue was redissolved in 5%MeOH in DCM and adsorbed onto Isolute. Purification was performed on aTeledyne-Isco Combiflash Rf purification system using a Redi-Sep 80 gsilica gel cartridge with gradient elution of 0% A in DCM to 100% A inDCM over a 40 min period (the first 5 min was holding time for 0% A inDCM, A was a 10/1 mixture of DCM/MeOH, flow rate at 60 mL/min, UV at 254nm). The appropriate fractions were combined and concentrated to givethe title compound (2.23 g) as a light pinkish solid.

LC/MS: m/z 243.8 (M+H)⁺, 0.47 min (ret. time).

¹HNMR (400 MHz, DMSO-d₆): δ 6.02 (s, 1H), 4.22-4.05 (m, 3H), 3.69-3.56(m, 1H), 3.29-3.16 (m, 1H), 2.94-2.81 (m, 1H), 2.81-2.67 (m, 2H),2.66-2.55 (m, 1H).

D67 (2R,4R)-1-((Benzyloxy)carbonyl)-4-hydroxypyrrolidine-2-carboxylicAcid

(2R,4R)-4-hydroxypyrrolidine-2-carboxylic acid (1.00 g, 7.63 mmol) wasadded to water (15.10 ml) followed by adding sodium bicarbonate (1.60 g,19.07 mmol). To this mixture was added a solution of benzylchloroformate (1.198 ml, 8.39 mmol) in toluene (3.77 mL) dropwise andthe reaction was allowed to stir at RT. After 12 h, reaction contentswere added to separatory funnel and separated the layers. Excess benzylchloroformate was removed by washing the aqueous layer with 5×6 mL Et₂O.Acidified the aqueous layer to pH=2 with the dropwise addition ofconcentrated HCl (37%), affording a white precipitate. Diluted with 30mL EtOAc and separated the resulting layers. The aqueous layer wasextracted with 6×10 mL EtOAc, and the combined organics were dried overNa₂SO₄, filtered and concentrated in vacuo to give(2R,4R)-1-((benzyloxy)carbonyl)-4-hydroxypyrrolidine-2-carboxylic acidas a white solid.

LC/MS: m/z 265.9 (M+H)⁺, 0.60 min (ret. time).

D68 (2R,4R)-1-Benzyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate

(2R,4R)-1-((benzyloxy)carbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(1.68 g, 6.33 mmol) was added to N,N-dimethylformamide (DMF) (10 ml)followed by the addition of sodium bicarbonate (1.064 g, 12.67 mmol).Added methyl iodide (1.980 ml, 31.7 mmol) dropwise and placed in a 50°C. bath. After 3 h, cooled to RT and partitioned between 150 mL EtOAcand 50 mL H₂O. The resulting layers were separated. The organic layerswere washed with 5×30 mL H₂O and 1×20 mL brine. The organics were driedover Na₂SO₄, filtered and concentrated in vacuo to give (2R,4R)-1-benzyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate a whitesolid.

LC/MS: m/z 279.9 (M+H)⁺, 0.71 min (ret. time).

D69 (2R,4R)-1-Benzyl 2-methyl4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate

(2R,4R)-1-benzyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (1.04g, 3.72 mmol) was added to DCM (18.62 ml) following by adding imidazole(0.507 g, 7.45 mmol) and TBSCl (0.730 g, 4.84 mmol). A white suspensionformed. After 12 h at RT, LCMS showed complete consumption of startingmaterial. Partitioned between 30 mL EtOAc and 20 mL H₂O and separatedthe resulting layers. The aqueous layer was back-extracted with 3×10 mLEtOAc. The combined organics were dried over Na₂SO₄, filtered andconcentrated in vacuo to give a pale yellow oil. Purification bynormal-phase HPLC (80 g CombiFlash column, 0-30% EtOAc:Hex) gave(2R,4R)-1-benzyl 2-methyl4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate as thick,colorless oil.

LC/MS: m/z 394.0 (M+H)⁺, 1.36 min (ret. time).

D70 (2R,4R)-Benzyl4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate

Dissolved (2R,4R)-1-benzyl 2-methyl4-((tert-butyldimethylsilyl)oxy)pyrrolidine-1,2-dicarboxylate (1.33 g,3.38 mmol) in THF (16.90 ml) and cooled to 0° C. Added DIBAL-H (1.5M intoluene) (1.923 g, 13.52 mmol) dropwise. The reaction was carried outfor 1.5 hours. The reaction mixture was quenched by adding to 100 mLsaturated Rochelle salts at RT, stirred for 16 h. The reaction mixturewas partitioned with 20 mL EtOAc, separated layers, and back-extractedaqueous with 3×5 mL EtOAc. The combined organics was dried over Na₂SO₄,filtered and concentrated in vacuo to give a clear, colorless oil. Thecrude material was dissolved in 2 mL DCM and purified by normal-phaseHPLC (40 g CombiFlash column, 0-50% EtOAc:Hex) to give (2R,4R)-benzyl4-((tert-butyldimethyl-silyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylateas a thick, colorless oil.

LC/MS: m/z 366.1 (M+H)⁺, 1.27 min (ret. time).

D71 ((2R,4R)-4-((tert-Butyldimethylsilyl)oxy)pyrrolidin-2-yl)methanol

Palladium on carbon (167 mg, 0.157 mmol) was added to (2R,4R)-Benzyl4-((tert-butyldimethylsilyl)oxy)-2-(hydroxymethyl)pyrrolidine-1-carboxylate(574.3 mg, 1.571 mmol) under N₂. Anhydrous methanol (7856 μl) was added,evacuated under vacuum and back-filled with H₂ (balloon, atmosphericpressure) for three times. The reaction mixture was allowed to stirunder H₂ at RT. After 3 h, the mixture was filtered through Celite, andwashed with MeOH and concentrated to give the title compound as orangeoil.

LC/MS: m/z 232.0 (M+H)⁺, 0.71 min (ret. time).

D72((2R,4R)-4-((tert-Butyldimethylsilyl)oxy)-1-(2,6-dichloropyrimidin-4-yl)pyrrolidin-2-yl)methanol

A solution of ((2R,4R)-4-((tert-Butyldimethylsilyl)oxy)pyrrolidin-2-yl)methanol (364 mg, 1.573 mmol) and TEA (658 μl, 4.72 mmol) intetrahydrofuran (THF) (3513 μl) was added dropwise via cannula to asolution of 2,4,6-trichloropyrimidine (181 μl, 1.573 mmol) in THF (3513μl) at −78° C. The reaction was allowed to gradually warm to RT. After14 h, the mixture was partitioned between 20 mL EtOAc and 10 mLsaturated NaHCO₃. The aqueous layer was back-extracted with 3×5 mLEtOAc. The combined organics were dried over Na₂SO₄, filtered andconcentrated. The crude was purified by normal-phase HPLC (24 gCombiFlash column, 0-30% EtOAc:Hex) to give the title compound as anoff-white solid.

LC/MS: m/z 380.0 (M+H)⁺, 1.29 min (ret. time).

D73 (7R,8aR)-7-((tert-Butyldimethylsilyl)oxy)-3-chloro-7,8,8a,9tetrahydropyrrolo[1′,2′:3,4] imidazo[1,2-c]pyrimidin-1(6H)-one

A solution of((2R,4R)-4-((tert-Butyldimethylsilyl)oxy)-1-(2,6-dichloropyrimidin-4-yl)pyrrolidin-2-yl)methanol(458.7 mg, 1.212 mmol) in DCM (5497 μl) was treated with TEA (845 μl,6.06 mmol) at RT. MsCl (283 μl, 3.64 mmol) was subsequently addeddropwise. After 20 min at RT, the mixture was concentrated in vacuo andthe resulting solid was suspended in acetonitrile (5497 μl). K₂CO₃ (503mg, 3.64 mmol) was added and the resulting suspension was heated to 80°C. The mixture was then partitioned the reaction mixture between 20 mLEtOAc and 15 mL saturated NaHCO₃. The aqueous layer was back-extractedwith 3×8 mL EtOAc. The combined organics were dried over Na₂SO₄,filtered and concentrated. The crude was purified by CombiFlash (2 4 g,0-100% EtOAc:Hex) to give the title compound as a white solid.

LC/MS: m/z 342.0 (M+H)⁺, 0.97 min (ret. time).

D74 tert-Butyl((3S,5R)-1-(2,6-dichloropyrimidin-4-yl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate

A solution of tert-butyl((3S,5R)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate hydrochloride (250mg, 0.989 mmol) and TEA (1103 μl, 7.91 mmol) in THF (1847 μl) was addeddropwise via syringe to a solution of 2,4,6-trichloropyrimidine (148 μl,1.286 mmol) in THF (1847 μl) at −78° C. The reaction was allowed togradually warm to RT and stirred for 30 min. The mixture was partitionedwith 10 mL EtOAc and 5 mL saturated NaHCO₃ and the resulting layers wereseparated. The aqueous layer was back-extracted with 3×5 mL EtOAc. Thecombined organics were dried Na₂SO₄, filtered and concentrated. Thecrude was purification by normal-phase HPLC (24 g CombiFlash column,0-50% EtOAc:Hex) to give the title compound as a white solid.

LC/MS: m/z 362.9 (M+H)⁺, 0.88 min (ret. time).

D75 tert-Butyl((7S,8aR)-3-chloro-1-oxo-1,6,7,8,8a,9-hexahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)carbamate

A solution of tert-Butyl((3S,5R)-1-(2,6-dichloropyrimidin-4-yl)-5-(hydroxymethyl)pyrrolidin-3-yl)carbamate(195.9 mg, 0.539 mmol) in DCM (2446 μl) was treated with TEA (376 μl,2.70 mmol). The resulting reaction mixture was subsequently cooled to 0°C. and MsCl (126 μl, 1.618 mmol) was added dropwise. The reaction wasallowed to gradually warm to RT and stirred for 20 min. The mixture wasconcentrated and suspended in acetonitrile (2446 μl). The resultingsuspension was treated with K₂CO₃ (224 mg, 1.618 mmol) and heated to 80°C. After 14 hrs, the reaction contents were partitioned between 15 mLEtOAc and 10 mL saturated NaHCO₃. The aqueous layer was back-extractedwith 3×5 mL EtOAc. The combined organics were dried over Na₂SO₄,filtered and concentrated. The crude was purification by normal-phaseHPLC (12 g CombiFlash column, 0-5% MeOH: DCM) to give the title compoundas a white solid.

LC/MS: m/z 327.0 (M+H)⁺, 0.67 min (ret. time).

D76 3-(Benzyloxy)-5-(trifluoromethyl)pyridine

To a mixture of NaH (159 mg, 6.61 mmol) in DMF (5 mL) was addedphenylmethanol (477 mg, 4.41 mmol). The solution was stirred at roomtemperature for 15 min and then 3-chloro-5-(trifluoromethyl)pyridine(800 mg, 4.41 mmol) was added in portion. The mixture was stirred atroom temperature for another 3 hrs. After added 20 mL water, the mixturewas extracted by EA (15 mL×3), washed with brine (20 mL×2) and dried togive the title compound (600 mg, 0.867 mmol, 19.67% yield).

LC-MS (ESI): m/z 254[M+H]⁺; 1.48 min (ret time).

D77 5-(Trifluoromethyl)pyridin-3-ol

A mixture of 3-(benzyloxy)-5-(trifluoromethyl)pyridine (600 mg, 2.369mmol) and Pd/C (252 mg, 0.2369 mmol, 10% wt) in methanol (5 mL) wasstirred under hydrogen for 3 hrs. After filtration, the title compound(300 mg, 0.727 mmol, 30.7% yield) was obtained without furtherpurification.

LC-MS (ESI): m/z 162[M−H]⁺; 1.30 min (ret time).

D78 5-Formyl-2-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile

A mixture of 5-(trifluoromethyl)pyridin-3-ol (300 mg, 1.839 mmol),2-fluoro-5 formylbenzonitrile (274 mg, 1.839 mmol) and K₂CO₃ (508 mg,3.68 mmol) in NMP (2 mL) was put in a vessel. The reaction vessel wassealed and heated in CEM Discover (microwave) to 120° C. for 1 hr. Aftercooling the reaction, the mixture was filtered off. After removing thesolvent under vacuo, the product gained without further purification wasused for nest step directly.

LC-MS (ESI): m/z 293[M+H]⁺; 1.64 min (ret time).

D795-(Hydroxymethyl)-2-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile

To a stirring solution of5-formyl-2-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile (220 mg,0.753 mmol) in methanol (15 mL) was added NaBH₄ (57.0 mg, 1.506 mmol) ina portion. The reaction mixture was kept stirring at room temperaturefor 3 hrs. Then acetone (5 mL) was added to quench this reaction. Afterremoving all the solvent under vacuo, silica gel chromatography was setup for purification using EA/PE=1:1 as elute to give the title compound(120 mg, 0.328 mmol, 43.5% yield) as yellow oil.

LC-MS (ESI): m/z 293[M−H]⁺; 1.23 min (ret time).

D80 2-Chloro-5-(2-fluoro-4-formylphenoxy)benzonitrile

To a solution of 2-chloro-5-hydroxybenzonitrile (2 g, 13.02 mmol) in DMF(30 mL) was added 3,4-difluorobenzaldehyde (1.851 g, 13.02 mmol) andK₂CO₃ (3.60 g, 26.0 mmol). The mixture was then stirred at 100° C. for16 hrs. After cooled to room temperature, the mixture was concentratedand the crude was purified by pre-TLC eluting with 25% EtOAc inpetroleum ether to give the title compound (130 mg, 0.472 mmol, 3.62%yield).

LC-MS (ESI): m/z 276[M+H]⁺; 1.22 min (ret time).

D81 2-Chloro-5-(2-fluoro-4-(hydroxymethyl)phenoxy)benzonitrile

The title compound was prepared by a procedure similar to that describedfor D79 starting from 2-chloro-5-(2-fluoro-4-formylphenoxy)benzonitrile(5.9 g, 21.40 mmol).

LC-MS (ESI): m/z 278[M+H]⁺; 1.65 min (ret time).

D82 5-Formyl-2-{[3-(trifluoromethyl)phenyl]oxy}benzonitrile

To a solution of 2-fluoro-5-formyl-benzonitrile (2.0 g, 13.41 mmol) and3-trifluoromethyl-phenol (1.63 mL, 13.41 mmol) in DMF (10 mL) was addedpotassium carbonate (1.85 g, 13.41 mmol). The reaction mixture wasstirred at 60° C. for 2 hrs under microwave. The resultant mixture wasfiltrated, concentrated and the crude was purification via FC to givethe title compound (3 g, 73% yield) as a white solid.

LC-MS (ESI): m/z 292[M+H]⁺; 3.38 min (ret time).

D83 5-(Hydroxymethyl)-2-{[3-(trifluoromethyl)phenyl]oxy}benzonitrile

To a solution of 5-formyl-2-{[3-(trifluoromethyl)phenyl]oxy}benzonitrile(5 g, 17.17 mmol) in methanol (30 mL) at 0° C. was added NaBH₄ (0.39 g,10.30 mmol). The mixture was then stirred at room temperature for 30min. The reaction mixture was quenched with acetone and concentrated.The crude was purification via ISCO system (DCM/MeOH: 20/1) to give thetitle compound (5.5 g) as clear oil.

LC-MS (ESI): m/z 294[M+H]⁺; 3.09 min (ret time).

¹H NMR (400 MHz, CDCl₃): δ 7.72 (s, 1H), 7.5 (m, 3H), 7.32 (s, 1H), 7.25(s, 1H), 6.92 (d, J=8.8 Hz, 1H), 4.72 (s, 2H).

D84 (3,4-Difluoro-5-methylphenyl)methanol

To the solution of 3,4-difluoro-5-methylbenzaldehyde (70 mg, 0.448 mmol)in methanol (2 mL) was added NaBH₄ (25.4 mg, 0.673 mmol). The solutionwas stirred at room temperature for 30 min. The reaction mixture wasdiluted with water and extracted with EA. The organic phase was washedwith brine, driver over Na₂SO₄, filtrated and evaporated in vacuo togive the title compound (35 mg, 0.221 mmol, 49.4% yield) as white solid.

D85 3-Fluoro-5-(hydroxymethyl)benzonitrile

To a solution of 3-cyano-5-fluorobenzoic acid (3 g, 18.17 mmol) intetrahydrofuran (THF) (60 mL) was added CDI (4.42 g, 27.3 mmol) at 0°C., after added, the mixture was stirred at 23° C. for 30 min, thecooled to 0° C. again, was added sodium borohydride (1.375 g, 36.3 mmol)drop wise, then which was stirred at 23° C. for 16 hrs, quenched withsaturated NH₄Cl aqueous, filtered, dried over Na₂SO₄, concentrated togive crude, which was purified by flash column (PE:EA=10:1) to give thetarget.

LC-MS (ESI): m/z 152 [M+H]⁺; 0.97 min (ret time).

¹H NMR (400 MHz, MeOD): δ 7.53 (m, 1H), 7.41 (m, 2H), 4.64 (d, 2H).

D86 (3-Chloro-4,5-difluorophenyl)methanol

A mixture of 3-chloro-4,5-difluorobenzoic acid (0.750 g, 3.90 mmol) andCDI (0.695 g, 4.28 mmol) in THF (10 mL) was stirred under nitrogen atroom temp for 1 h. Then a solution of NaBH₄ (0.221 g, 5.84 mmol) inwater (2.0 mL) was added drop wise. The reaction mixture was stirred at10° C. for 16 hrs, adjusted to pH=1 with 1 M HCl solution, concentratedto remove THF, and extracted with ethyl acetate. The organic part waswashed with a solution of NaHCO₃ and concentrated. Purification viapreparative TLC afforded the title product.

LC-MS (ESI): m/z179 [M+H]⁺; 1.10 min (ret time).

¹H NMR (400 MHz, CDCl₃): δ 7.15-7.13 (m, 1H), 7.11-7.04 (m, 2H),4.63-4.56 (t, 2H), 2.57 (s, 1H).

D87 3-Fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzaldehyde

The title compound was prepared by a procedure similar to that describedfor D80 starting from 3,4-difluorobenzaldehyde and2-(trifluoromethyl)pyridin-4-ol.

LC-MS (ESI): m/z 286 [M+H]⁺; 0.81 min (ret time).

D88 3-Fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D79 starting from3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzaldehyde.

LC-MS (ESI): m/z 288 [M+H]⁺; 0.76 min (ret time).

D89 4-(3,4-Difluorophenoxy)-3-fluorobenzaldehyde

A mixture of 3,4-difluorobenzaldehyde (400 mg, 2.81 mmol),3,4-difluorophenol (366 mg, 2.81 mmol) and K₂CO₃ (778 mg, 5.63 mmol) wasput in a vessel. The reaction vessel was sealed and heated in CEMDiscover using initial normal to 120° C. for 1 hr. After cooling thereaction, the mixture was filtered off. After removing the solvent undervacuo, the product gained without further purification was used for neststep directly.

LC-MS (ESI): m/z 252 [M+H]⁺; 1.72 min (ret time).

D90 (4-(3,4-Difluorophenoxy)-3-fluorophenyl)methanol

To a stirring solution of 4-(3,4-difluorophenoxy)-3-fluorobenzaldehyde(220 mg, 0.872 mmol) in methanol (15 mL) was added NaBH₄ (33.0 mg, 0.872mmol) in a portion. The reaction mixture was kept stirring at r.t. for 3hrs. Then acetone (5 mL) was added to quench this reaction. Afterremoving all the solvent under vacuo, silica gel chromatography was setup for purification using EA/PE=1:1 as elute to get(4-(3,4-difluorophenoxy)-3-fluorophenyl)methanol (100 mg, 0.263 mmol,30.1% yield) as yellow oil.

LC-MS (ESI): m/z 253 [M−H]⁺; 1.68 min (ret time).

D91 2-(3,4-Difluorophenoxy)-5-formylbenzonitrile

A mixture of 2-fluoro-5-formylbenzonitrile (300 mg, 2.012 mmol),3,4-difluorophenol (288 mg, 2.213 mmol) and potassium carbonate (556 mg,4.02 mmol) was put in a vessel. The reaction vessel was sealed andheated in CEM Discover using initial normal to 120° C. for 1 hr. Aftercooling the reaction, the mixture was filtered off. After removing thesolvent under vacuo, the product gained without further purification wasused for nest step directly.

LC-MS (ESI): m/z 260 [M+H]⁺; 1.47 min (ret time).

D92 2-(3,4-Difluorophenoxy)-5-(hydroxymethyl)benzonitrile

To a stirring solution of 2-(3,4-difluorophenoxy)-5-formylbenzonitrile(400 mg, 1.543 mmol) in methanol (12 mL) was added NaBH₄ (58.4 mg, 1.543mmol) in a portion. The reaction mixture was kept stirring at r.t. for 3h. Then acetone (5 mL) was added to quench this reaction. After removingall the solvent under vacuo, silica gel chromatography was set up forpurification using EA/PE=1:1 as elute to get2-(3,4-difluorophenoxy)-5-(hydroxymethyl)benzonitrile (300 mg, 1.100mmol, 71.3% yield) as yellow oil.

LC-MS (ESI): m/z 260 [M−H]⁺; 1.62 min (ret time).

D93 2-Chloro-4-(2-cyano-4-formylphenoxy)benzonitrile

The title compound was prepared by a procedure similar to that describedfor D80 starting from 2-fluoro-5-formylbenzonitrile and2-chloro-4-hydroxybenzonitrile.

LC-MS (ESI): m/z 283 [M+H]⁺; 3.07 min (ret time)

D94 2-Chloro-4-(2-cyano-4-(hydroxymethyl)phenoxy)benzonitrile

The title compound was prepared by a procedure similar to that describedfor D79 starting from 2-chloro-4-(2-cyano-4-formylphenoxy)benzonitrile.

LC-MS (ESI): m/z 285 [M+H]⁺; 2.79 min (ret time)

D957-((3,5-Difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one

The title compound was prepared by a procedure similar to that describedfor D80 starting from 5-(trifluoromethyl)pyridin-3-ol and3,4,5-trifluorobenzaldehyde.

LC-MS (ESI): m/z 303 [M+H]⁺; 1.22 (ret time).

D96(3,5-Difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D79 starting from3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzaldehyde.

LC-MS (ESI): m/z 306 [M+H]⁺; 0.93 (ret time).

D97 3-Fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzaldehyde

To the solution of 3,4-difluorobenzaldehyde (500 mg, 3.52 mmol) and6-(trifluoromethyl)pyridin-3-ol (574 mg, 3.52 mmol) in acetonitrile (10ml), was added K₂CO₃ (729 mg, 5.28 mmol). The reaction mixture wassealed and heated in Biotage Initiator using initial normal to 130° C.for 4 h. After cooling the reaction, the reaction mixture was filtratedand evaporated in vacuo to give3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzaldehyde (903 mg,3.17 mmol, 90% yield) as brown solid.

D98 (3-Fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol

To the solution of 3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzaldehyde (900 mg, 3.16 mmol) in methanol (12 ml),was added NaBH₄ (179 mg, 4.73 mmol). The solution was stirred at rt for10 min. The reaction mixture was partition between water and EA. Theorganic phase was washed with brine, dried over Na₂SO₄ and evaporated invacuo to give crude product(3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol (480mg, 1.671 mmol, 53.0% yield) as black oil.

LC-MS (ESI): m/z 288 [M+H]⁺; 2.88 min (ret time).

D99 5-Formyl-2-(4-(trifluoromethyl)phenoxy)benzonitrile

The title compound was prepared by a procedure similar to that describedfor D80 starting from 2-fluoro-5-formylbenzonitrile and4-(trifluoromethyl)phenol.

LC-MS (ESI): m/z 292 [M+H]⁺; 3.41 min (ret time).

D100 5-(Hydroxymethyl)-2-(4-(trifluoromethyl)phenoxy)benzonitrile

The title compound was prepared by a procedure similar to that describedfor D79 starting from5-(hydroxymethyl)-2-(4-(trifluoromethyl)phenoxy)benzonitrile.

LC-MS (ESI): m/z 294 [M+H]⁺; 3.13 min (ret time).

D101 2-(4-Chloro-3-fluorophenoxy)-5-formylbenzonitrile

The title compound was prepared by a procedure similar to that describedfor D80 starting from 2-fluoro-5-formylbenzonitrile and4-chloro-3-fluorophenol.

LC-MS (ESI): m/z 276 [M+H]⁺; 3.33 min (ret time)

D102 2-(4-Chloro-3-fluorophenoxy)-5-(hydroxymethyl) benzonitrile

The title compound was prepared by a procedure similar to that describedfor D79 starting from 2-(3-chloro-4-fluorophenoxy)-5-formylbenzonitrile.

LC-MS (ESI): m/z 278 [M+H]⁺; 3.02 min (ret time)

D103 3,5-Difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzaldehyde

The title compound was prepared by a procedure similar to that describedfor D80 starting from 2,4,5-trifluorobenzaldehyde and6-(trifluoromethyl)pyridin-3-ol.

LC-MS (ESI): m/z 304 [M+H]⁺; 3.29 min (ret time).

D104(3,5-Difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D79 starting3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzaldehyde.

LC-MS (ESI): m/z 306 [M+H]⁺; 3.03 min (ret time)

D105 4-((2-Chloropyridin-4-yl)oxy)-3,5-difluorobenzaldehyde

A mixture of 3,4,5-trifluorobenzaldehyde (500 mg, 3.12 mmol),2-chloropyridin-4-ol (405 mg, 3.12 mmol) and K₂CO₃ (647 mg, 4.68 mmol)in acetonitrile (10 mL) was sealed in a microwave vial and irradiatedwith a microwave using initial normal to 130° C. for 1 h, then filteredand concentrated to give the crude as brown oil.

LCMS (ESI): m/z 270 [M+H]⁺; 3.02 min (ret time)

D106 (4-((2-Chloropyridin-4-yl)oxy)-3,5-difluorophenyl)methanol

To a solution of 4-((2-chloropyridin-4-yl)oxy)-3,5-difluorobenzaldehyde(746 mg, 2.77 mmol) in methanol (8 mL) was added NaBH₄ (157 mg, 4.15mmol). The reaction mixture was stirred at rt for 10 min., andpartitioned between water and ethyl acetate. Organic part was washedwith brine, dried over anhydrous Na₂SO₄ and evaporated in vacuo to givethe crude as brown oil.

LCMS (ESI): m/z 272 [M+H]⁺; 2.69 min (ret time)

D107 3-(2-Fluoro-4-formylphenoxy)-5-(trifluoromethyl)benzonitrile

To the solution of 3,4-difluorobenzaldehyde (150 mg, 1.056 mmol) and3-hydroxy-5-(trifluoromethyl)benzonitrile (198 mg, 1.056 mmol) inacetonitrile (3 ml), was added K₂CO₃ (219 mg, 1.583 mmol). The reactionmixture was sealed and heated in Biotage Initiator using under 130° C.for 1 h. After cooling the reaction, the reaction mixture was filtratedand evaporated in vacuo to give3-(2-fluoro-4-formylphenoxy)-5-(trifluoromethyl)benzonitrile (294 mg,0.950 mmol, 90% yield) as brown oil.

D1083-(2-Fluoro-4-(hydroxymethyl)phenoxy)-5-(trifluoromethyl)benzonitrile

To the solution of3-(2-fluoro-4-formylphenoxy)-5-(trifluoromethyl)benzonitrile (290 mg,0.938 mmol) in methanol (4 ml), was added NaBH₄ (53.2 mg, 1.407 mmol).The solution was stirred at rt for 10 min. The reaction mixture waspartition between water and EA. The organic phase was washed with brine,dried over Na₂SO₄ and evaporated in vacuo to give crude product3-(2-fluoro-4-(hydroxymethyl)phenoxy)-5-(trifluoromethyl)benzonitrile(280 mg, 0.900 mmol, 96% yield) as brown oil.

D109 3,5-Difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzaldehyde

To a solution of 2-(trifluoromethyl)pyridin-4-ol (1.019 g, 6.25 mmol)and K₂CO₃ (1.727 g, 12.49 mmol) in acetonitrile (250 mL) stirred undernitrogen at 20° C. was added a solution of 3,4,5-trifluorobenzaldehyde(1 g, 6.25 mmol) in acetonitrile (50 mL) dropwise during 5 min. Thereaction mixture was stirred at 70° C. for 18 hrs. The reaction mixturewas diluted with ethyl acetate (20 mL) and the organic phase was washedwith water (2×20 mL), saturated brine (20 mL), dried over sodiumsulphate and evaporated in vacuo to give the title compound (2.0 g, 6.02mmol, 96% yield) as a brown gum.

LC-MS (ESI): m/z 304 [M+H]⁺; 3.64 min (ret time).

An alternative process of preparing the compound is provided: To asolution of 3,4,5-trifluorobenzaldehyde (2356 mg, 14.72 mmol) and2-(trifluoromethyl)pyridin-4-ol (2000 mg, 12.26 mmol) inN,N-dimethylformamide (6 mL), K₂CO₃ (3390 mg, 24.53 mmol) was added. Themixture was irradiated with a microwave at 110° C. and stirred for 3 h,and concentrated. The crude product was washed with EtOAc, and thenfiltered. The organic phase was concentrated to afford the titlecompound (4 g, 6.86 mmol, 55.9% yield) as a oil.

LC-MS (ESI): m/z 304 [M+H]⁺; 1.06 min (ret time).

D110(3,5-Difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol

To a solution of3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzaldehyde (50 g,165 mmol) in methanol (400 mL) was added NaBH₄ (3.12 g, 82 mmol) at 0°C. for 10 min. The reaction progress was monitored by TLC and mobilephase was 30% EtOAc in PE. The reaction mixture was quenched with icewater (200 mL) and evaporated under reduced pressure to remove methanoland crude was diluted with ethyl acetate (200 mL) and water (200 mL),organic layer was separated and washed with brine solution (100 mL),dried over Na₂SO₄ and evaporated completely afforded crude product 50 g,washed with PE and dried to afford the title compound (45 g, 144 mmol,88% yield) as a white solid.

LC-MS (ESI): m/z 306 [M+H]⁺; 2.13 min (ret time).

Another exemplary process is provided as: to a solution of3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzaldehyde (4000mg, 13.19 mmol) in methanol (30 mL) was added NaBH₄ (250 mg, 6.60 mmol)at 0° C. for 10 min in portion. The reaction mixture was stirred at 5°C. for 0.5 h, concentrated, and dissolved in water, then extracted withEtOAc. The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄, filtered, and concentrated. The crude product waspurified by silica gel column (PE/EtOAc 5:1 to 1:1) to afford the titlecompound (3900 mg, 12.61 mmol, 96% yield) as a white solid.

LC-MS (ESI): m/z 306 [M+H]⁺; 1.65 min (ret time).

D111 3-Fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzaldehyde

To a solution of 3,4-difluorobenzaldehyde (436 mg, 3.07 mmol) in DMF (30mL) was added 5-(trifluoromethyl)pyridin-3-ol (500 mg, 3.07 mmol), K₂CO₃(847 mg, 6.13 mmol) was added to the mixture, then the mixture wasstirred at 100° C. for 16 hrs, concentrated to give the crude, purifiedby pre-TLC eluting with 25% EtOAc in petroleum ether to give the3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzaldehyde (298 mg,1.045 mmol, 34.1% yield).

LC-MS (ESI): m/z 286 [M+H]⁺; 1.50 min (ret time).

D112 (3-Fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol

To a solution of3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzaldehyde (298 mg,1.045 mmol) in methanol (5 mL) stirred under nitrogen was added solidNaBH₄ (44.4 mg, 1.174 mmol) portionwise at 0° C. The reaction mixturewas stirred at 23° C. for 16 hrs, quenched with saturated NH₄Clsolution, the solution was extracted by EtOAc (3×20 mL), and the organicwas dried with anhydrous Na₂SO₄, concentrated to give the targetcompound (3-fluoro-4-((5(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol (126 mg, 0.439 mmol,42.0% yield) which was used in the next reaction without furtherpurification.

LC-MS (ESI): m/z 288 [M+H]⁺; 1.24 min (ret time).

D113 2-Fluoro-4-(hydroxymethyl)phenol

The title compound was prepared by a procedure similar to that describedfor D79 starting from 3-fluoro-4-hydroxybenzaldehyde.

D114 (3-Fluoro-4-((2-(trifluoromethyl) pyrimidin-5-yl) oxy) phenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D80 starting from 5-bromo-2-(trifluoromethyl)pyrimidine and2-fluoro-4-(hydroxymethyl)phenol.

LC-MS (ESI): m/z 289[M+H]⁺; 0.99 min (ret time).

¹H NMR (400 MHz, CDCl₃): δ 8.52 (s, 2H), 7.32 (d, 1H), 7.25-7.20 (m,2H), 4.76 (s, 2H).

D115 1-Methyl-1H-pyrazol-4-ol

To a solution of1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(100 mg, 0.481 mmol) in THF (20 mL) was added hydrogen peroxide (32.7mg, 0.961 mmol) and sodium hydroxide (38.4 mg, 0.961 mmol) at 0° C. andstirred at this temperature for 3 min then warmed to room temperature(5° C.) for further 50 min. The reaction was diluted with wateracidified with HCl (2N) and extracted four times with DCM and four timeswith DCM/isopropanol (4:1). The combined organic layers were dried overNa₂SO₄, filtered and concentrated to give the title compound (30 mg,38.2% yield) as yellow oil.

¹H NMR (400 MHz, CDCl₃): δ 7.13 (s, 1H), 7.03 (s, 1H), 3.77 (s, 3H).

D116 3,5-Difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzaldehyde

The mixture of 3,4,5-trifluorobenzaldehyde (1958 mg, 12.23 mmol), K₂CO₃(2818 mg, 20.39 mmol) and 1-methyl-1H-pyrazol-4-ol (1000 mg, 10.19 mmol)in DMF (6 mL) was sealed in a tube and heated to 110° C. by microwavefor 3 hrs. The reaction mixture was concentrated to get the crudeproduct which was treated with EtOAc, the solid was filtered off and theorganic phase was concentrated to give the title compound (800 mg, 26.4%yield) as oil.

LC-MS (ESI): m/z 239 [M+H]⁺; 0.9 min (ret time).

D117 (3,5-Difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)methanol

To a solution of3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzaldehyde (800 mg, 3.36mmol) in methanol (30 mL) was added portion wise sodium tetrahydroborate(127 mg, 3.36 mmol) at 0° C. then warm to 5° C. for 0.5 h. The solventwas removed and treated with water then extracted with ethyl acetate.Combined organic parts were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated to get the crude product which waspurified by silica gel column eluting with petroleum ether/EtOAc(5:1-1:1) to give the title compound (495 mg, 97% yield) as a whitesolid.

LC-MS (ESI): m/z 241 [M+H]⁺; 1.23 min (ret time).

D118 3-Fluoro-4-((1-methyl-1Hpyrazol-4-yl) oxy) benzaldehyde

The title compound was prepared by a procedure similar to that describedfor D116 starting from 3, 4-difluorobenzaldehyde and1-methyl-1H-pyrazol-4-ol.

LC-MS (ESI): m/z 221 [M+H]⁺; 1.21 min (ret time).

D119 (3-Fluoro-4-((1-methyl-1Hpyrazol-4-yl) oxy) phenyl) methanol

The title compound was prepared by a procedure similar to that describedfor D117 starting from 3-fluoro-4-((1-methyl-1 Hpyrazol-4-yl) oxy)benzaldehyde.

LC-MS (ESI): m/z 223[M+H]⁺; 1.17 min (ret time).

D120 1-(4-Bromo-2,6-difluorophenoxy)cyclopropanecarbaldehyde

To a solution of (1-(4-bromo-2,6-difluorophenoxy)cyclopropyl)methanol(5.0 g, 18.0 mmol) in DCM (100 mL) was added Dess-Martin periodinane(11.4 g, 27.0 mmol) portionwise at 0° C. The mixture was stirred at roomtemperature overnight, and then diluted with DCM (100 mL). The organicphase was separated, washed with sat. NaHCO₃ (100 mL), sat. Na₂SO₃ (100mL) and brine, dried over Na₂SO₄, concentrated and purified by flashchromatography column (PE/EA=40/1) to give title compound (6.8 g, 90.2%)as colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 9.92 (s, 1H), 7.12 (m, 2H), 1.46 (m, 4H).

D121 5-Bromo-1,3-difluoro-2-(1-vinylcyclopropoxy)benzene

To a solution of bromo(methyl)triphenylphosphorane (2.58 g, 7.20 mmol)in THF (20 mL) was added LiN[Si(CH₃)₃]₂ (1 M in THF, 7.90 mL, 7.90 mmol)dropwise at −78° C. and the solution was stirred at the same temperaturefor 30 min. Then 1-(4-bromo-2,6-difluorophenoxy)cyclopropanecarbaldehyde(1.0 g, 3.6 mmol) in THF (2.0 mL) was added into above solution at −78°C. dropwise. The mixture was stirred at room temperature for 2 hours,quenched with water (20 mL) and the solution was separated. The aqueouswas extracted with EtOAc (20 mL×2). The combined organic phases werewashed with brine, dried over Na₂SO₄, filtered, concentrated andsubjected to flash chromatography column (PE/EA=50/1) to give titlecompound (500 mg, 51%) as colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 7.06 (m, 2H), 6.02 (dd, J=17.4, 10.8 Hz, 1H),5.09 (m, 2H), 1.27 (m, 2H), 0.92 (m, 2H).

D122 2-(1-(4-Bromo-2,6-difluorophenoxy)cyclopropyl)ethanol

To a solution of 5-bromo-1,3-difluoro-2-(1-vinylcyclopropoxy)benzene(500 mg, 1.82 mmol) in THF (5 mL) was added 9-BBN (0.5 M in THF, 7.30mL, 3.65 mmol) at room temperature and the solution was stirred at thesame temperature for 2 hours until no starting material was detected byTLC. Aqueous NaOH solution (3.0 M, 0.91 mL, 2.73 mmol) was added intoabove solution, followed by H₂O₂ (30% in water, 1.1 mL, 9.1 mmol) at 0°C. The mixture was then stirred at room temperature for 1 hour, dilutedwith brine (20 mL) and then extracted with EtOAc (30 ml×3). The organicphase was dried over Na₂SO₄, filtered, concentrated and subjected toflash chromatography column (PE/EA=20/1 and 3/1) to give title compound(400 mg, 75%) as colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 7.08 (m, 2H), 3.98 (t, J=5.7 Hz, 2H), 2.00(t, J=5.7 Hz, 2H), 1.01 (m, 2H), 0.65 (m, 2H).

D123 2-(1-(4-Bromo-2,6-difluorophenoxy)cyclopropyl)ethyl4-methylbenzenesulfonate

To a solution of 2-(1-(4-bromo-2,6-difluorophenoxy)cyclopropyl)ethanol(290 mg, 1.00 mmol), Et₃N (300 mg, 3.00 mmol) and DMAP (20 mg) in DCM (5mL) was added chloro(4-methylphenyl)sulfone (285 mg, 1.50 mmol) at 0° C.The mixture was stirred at room temperature for 2 hours. The reactionsolution was diluted with DCM (30 mL) and then washed with water (30mL), 1N HCl (30 mL) and brine, successively. The organic phase was driedover Na₂SO₄, filtered, concentrated and subjected to flashchromatography column (PE/EA=20/1) to give title compound (220 mg, 49%)as colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 7.81 (d, J=8.1 Hz, 2H), 7.34 (d, J=8.1 Hz,2H), 7.04 (m, 2H), 4.37 (d, J=7.2 Hz, 2H), 2.45 (s, 3H), 2.07 (t, J=7.2Hz, 2H), 1.00 (m, 2H), 0.61 (m, 2H).

D124 5-Bromo-1,3-difluoro-2-(1-(2-fluoroethyl)cyclopropoxy)benzene

A solution of 2-(1-(4-bromo-2,6-difluorophenoxy)cyclopropyl)ethyl4-methylbenzenesulfonate (220 mg, 0.49 mmol) and TBAF (1 M in THF, 2.5mL, 2.5 mmol) in THF (5.0 mL) was stirred at 110° C. in a sealed vialfor 3 hours. The reaction solution was diluted with EtOAc (30 mL) andthen washed with 1N HCl (30 mL), brine successively. The organic layerwas dried over Na₂SO₄, filtered, concentrated and purified by Prep-TLC(PE/EA=20/1) to give title compound (70 mg, 49%) as colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 7.08 (m, 2H), 4.76 (dt, J=47.1, 6.3 Hz, 2H),2.14 (dt, J=22.5, 6.3 Hz, 2H), 1.07 (m, 2H), 0.67 (m, 2H).

D125 Ethyl 3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)benzoate

A mixture of5-bromo-1,3-difluoro-2-(1-(2-fluoroethyl)cyclopropoxy)benzene (400 mg,1.36 mmol), KOAc (267 mg, 2.72 mmol) and Pd(dppf)Cl₂ (99 mg, 0.14 mmol)in EtOH (5 mL) was stirred at 80° C. under CO (1 atm) for 2 hours. Thereaction solution was filtered. The filtrate was concentrated andsubjected to flash chromatography column (PE/EA=30/1) to give the titlecompound (300 mg, 79.3%) as colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 7.59 (m, 2H), 4.75 (dt, J=46.8, 6.0 Hz, 2H),4.36 (q, J=6.9 Hz, 2H), 2.18 (dt, J=22.8, 6.0 Hz, 2H), 1.38 (t, J=6.9Hz, 3H), 1.09 (m. 2H), 0.74 (m, 2H).

D126 (3,5-Difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)phenyl)methanol

To a solution of ethyl 3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)benzoate (310 mg, 1.10mmol), in THF (20 mL) was added LiAlH₄ (61.0 mg, 1.64 mmol) portionwiseat 0° C. The reaction mixture was stirred at 0° C. for another 1 hour.The reaction was then quenched with sat. Na₂SO₄ (10 mL) and thesuspension was filtered. The filtrate was diluted with EtOAc (30 mL) andthen washed with brine. The organic phase was dried over Na₂SO₄,filtered and concentrated to give the crude title compound (210 mg, 79%)as colorless oil, which was used for the next reaction withoutpurification.

¹H NMR (300 MHz, CDCl₃): δ 6.92 (m, 2H), 4.79 (dt, J=46.8, 6.6 Hz, 2H),2.14 (dt, J=22.5, 6.6 Hz, 2H), 1.09 (m, 2H), 0.66 (m, 2H).

D127 1-Ethyl-1H-pyrazol-4-ol

To the suspension of NaH (1.855 g, 77 mmol) in tetrahydrofuran (THF)(100 mL), a solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10 g, 51.5mmol) in THF (15 mL) was added dropwise at 0° C. under N₂ atmosphere.The result mixture was stirred for 30 minutes and then iodoethane (16.08g, 103 mmol) was added. The result solution was stirred and left warm toroom temperature overnight, filtered and the filtrate was added 15% NaOHaqueous (30 mL), then H₂O₂ (12 mL, 30%, 105 mmol, 2.1 eq) after thereaction mixture was cooled to 0° C. under ice-salt bath. The reactionmixture was stirred for another 1 hour then extracted with EtOAc (200mL×2), and the water phase was acidified with concentrated HCl aqueousto pH=1˜2, extracted with EtOAc (200 ml×5), the combined organic phasewas washed with water 20 mL, dried over MgSO₄, concentrated to give thetitle compound (4.2 g, 72.7% yield) as yellow oil.

LC-MS (ESI): m/z 113 [M+H]⁺; 0.45 min (ret time).

D128 4-(1-Ethyl-1H-pyrazol-4-yloxy)-3,5-difluorobenzaldehyde

The reaction tube containing 3,4,5-trifluorobenzaldehyde (2.86 g, 17.84mmol), K₂CO₃ (2.465 g, 17.84 mmol), 1-ethyl-1H-pyrazol-4-ol (2.0 g,17.84 mmol) and DMF (20 mL) was sealed and heated to 110° C. for 3 hoursunder microwave. The reaction mixture was cooled and diluted by EtOAc(500 mL), washed with brine (25 mL×6), dried over MgSO₄, concentrated toget the crude product which was purified with silica gel column, elutingwith PE/EtOAc=10 to give the title compound (3.7 g, 41.1%) as yellowoil.

LC-MS (ESI): m/z 253 [M+H]⁺; 1.54 min (ret time).

D129 (4-(1-Ethyl-1H-pyrazol-4-yloxy)-3,5-difluorophenyl)methanol

To the solution of4-((1-ethyl-1H-pyrazol-4-yl)oxy)-3,5-difluorobenzaldehyde (3.5 g, 13.88mmol) in methanol (50 mL) was added NaBH₄ (0.263 g, 6.94 mmol) at 0° C.After 20 minutes, the reaction was quenched with water 100 mL. Methanolwas removed and the residue was extracted with EtOAc (25 mL×2), theorganic phase was dried over MgSO₄, concentrated to get the crudeproduct which was purified by silica gel column, eluting withPE/EtOAc=5/1 to give impurity product which was washed by Petroleumether (30 mL) to give the title compound (2.1 g, 8.26 mmol, 59.5% yield)as a light yellow solid.

LC-MS (ESI): m/z 255 [M+H]⁺; 1.43 min (ret time).

D130 1-Isopropyl-1H-pyrazol-4-ol

To the suspension of NaH (0.309 g, 7.73 mmol) in THF (20 mL) was added asolution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1 g, 5.15 mmol) in THF (1.5 mL) at 0° C. under N₂ atmosphere. Theresulting mixture was stirred for 30 min and then 2-iodopropane (1.752g, 10.31 mmol) was added. The result solution was stirred and left warmto room temperature for 8 hrs. The reaction mixture was diluted withEtOAc (100 mL), filtered and the filtrate was concentrated. The crudeproduct was dissolved in THF (20 mL) and cooled to 0° C. under ice-brinebath. Then H₂O₂ (1 mL, 30 wt %) was added dropwise, followed by dropwiseaddition of 2N NaOH aqueous. After stirred for 2 hours, the reaction wasquenched with 20 mL of water, acidified to pH=6˜7, extracted with DCM(100 mL×2). The combined organic phase was dried over MgSO₄ andconcentrated to give the title compound (850 mg, 4.01 mmol, 78% yield)as yellow oil.

LC-MS (ESI): m/z 127 [M+H]⁺; 0.65 min (ret time).

D131 3,5-Difluoro-4-((1-isopropyl-1H-pyrazol-4-yl)oxy)benzaldehyde

A mixture of 3,4,5-trifluorobenzaldehyde (800 mg, 5.00 mmol) and1-isopropyl-1H-pyrazol-4-ol (850 mg, 4.04 mmol) and K₂CO₃ (690 mg, 5mmol) was dissolved in DMF (20 mL) and sealed with a tube. The resultingmixture was stirred and heated to 110° C. for 3 hours in microwave. Thereaction mixture was cooled and diluted with EtOAc (300 mL) andsaturated NH₄Cl aqueous (30 mL), the organic phase was washed with brine(25 mL×6), dried over MgSO₄, concentrated. The crude product waspurified with silica gel column, eluenting with petroleumether/EtOAc=3/1.

LC-MS (ESI): m/z 267 [M+H]⁺; 1.61 min (ret time).

D132 (3,5-Difluoro-4-((1-isopropyl-1H-pyrazol-4-yl)oxy)phenyl)methanol

To the solution of 3,5-difluoro-4-((1-isopropyl-1H-pyrazol-4-yl)oxy)benzaldehyde in methanol(5 mL) cooled to 0° C. in ice-brine bathe, NaBH₄ (95 mg, 2.5 mmol) wasadded portions. The result was stirred for 20 minutes and quenched with10 mL of water. After the solvent was removed, the residue was extractedwith EtOAc (30 mL×3). The combined organic phase was dried over MgSO₄,and concentrated to get the crude product.

LC-MS (ESI): m/z 269 [M+H]⁺; 1.49 min (ret time).

D133 4-(3,4-Difluorophenoxy)-3,5-difluorobenzaldehyde

The title compound was prepared by a procedure similar to that describedfor D80 starting from 3,4,5-trifluorobenzaldehyde and3,4-difluorophenol.

LC-MS (ESI): m/z 271 [M+H]⁺; 1.76 min (ret time).

D134 (4-(3,4-Difluorophenoxy)-3,5-difluorophenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D79 starting from 4-(3,4-difluorophenoxy)-3,5-difluorobenzaldehyde.

LC-MS (ESI): m/z 273[M+H]⁺; 1.66 min (ret time).

D135 2-Chloro-5-(dibromomethyl)-3-fluoropyridine

A suspension of 2-chloro-3-fluoro-5-methylpyridine (5.0 g, 34.3 mmol),dibenzoyl peroxide (1.109 g, 3.43 mmol) and NBS (18.34 g, 103 mmol) inCCl₄ (100 mL) was refluxed for overnight, then cooled to rt and washedwith water and brine, dried over sodium sulfate, and concentrated.Purification via ISCO system afforded the title product (8.2 g) as abrown solid.

LC-MS (ESI): m/z 300 [M+H]⁺; 3.25 min (ret time).

D136 6-Chloro-5-fluoro-3-pyridinecarbaldehyde

A suspension 2-chloro-5-(dibromomethyl)-3-fluoropyridine (2.3 g, 7.58mmol), silver nitrate (5.15 g, 30.3 mmol) in a mixed solvents of ethanol(10 mL) and water (10 mL) was stirred for 1 h at 100° C., thenfiltrated, and concentrated. The residue was dissolved in ethyl acetate,washed with water and brine, dried over sodium sulfate, andconcentrated. Purification via ISCO system afforded the title product(1.0 g) as a pale solid.

LC-MS (ESI): m/z 159 [M+H]⁺; 2.01 min (ret time).

D1376-{[4-Chloro-3-(trifluoromethyl)phenyl]oxy}-5-fluoro-3-pyridinecarbaldehyde

The title compound was prepared by a procedure similar to that describedfor D80 starting from 6-chloro-5-fluoro-3-pyridinecarbaldehyde and4-chloro-3-(trifluoromethyl)phenol.

LC-MS (ESI): m/z 320 [M+H]⁺; 3.62 min (ret time).

D138(6-{[4-Chloro-3-(trifluoromethyl)phenyl]oxy}-5-fluoro-3-pyridinyl)methanol

The title compound was prepared by a procedure similar to that describedfor D79 starting from6-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-fluoro-3-pyridinecarbaldehyde.

LC-MS (ESI): m/z 322 [M+H]⁺; 3.52 min (ret time).

D139 2-(4-Chloro-3-(trifluoromethyl)phenoxy)-5-formylbenzonitrile

The title compound was prepared by a procedure similar to that describedfor D80 starting from 2-fluoro-5-formylbenzonitrile and4-chloro-3-(trifluoromethyl)phenol.

LC-MS (ESI): m/z 326 [M+H]⁺; 1.84 min (ret time).

D1402-(4-Chloro-3-(trifluoromethyl)phenoxy)-5-(hydroxymethyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor D79 starting from2-(4-chloro-3-(trifluoromethyl)phenoxy)-5-formylbenzonitrile.

LC-MS (ESI): m/z 328 [M+H]⁺; 1.68 min (ret time).

D141 3,5-Difluoro-4-(3-(trifluoromethyl)phenoxy)benzaldehyde

The title compound was prepared by a procedure similar to that describedfor D80 starting from 3,4,5-trifluorobenzaldehyde and3-(trifluoromethyl)phenol.

LC-MS (ESI): m/z 305 [M+H]⁺; 3.36 min (ret time).

D142 (3,5-Difluoro-4-(3-(trifluoromethyl)phenoxy)phenyl)methanol

The title compound was prepared by a procedure similar to that describedfor D79 starting from3,5-difluoro-4-(3-(trifluoromethyl)phenoxy)benzaldehyde.

LC-MS (ESI): m/z 305 [M+H]⁺; 3.36 min (ret time).

D143 6-(4-Chloro-3-(trifluoromethyl)phenoxy)nicotinaldehyde

The title compound was prepared by a procedure similar to that describedfor D80 starting from 6-chloronicotinaldehyde and4-fluoro-3-(trifluoromethyl)phenol.

LC-MS (ESI): m/z 286 [M+H]⁺; 3.34 min (ret time)

D144 (6-(4-Fluoro-3-(trifluoromethyl)phenoxy)pyridin-3-yl)methanol

The title compound was prepared by a procedure similar to that describedfor D79 starting from6-(4-fluoro-3-(trifluoromethyl)phenoxy)nicotinaldehyde.

LC-MS (ESI): m/z 288 [M+H]⁺; 2.90 min (ret time)

D145 2-(3-Fluorophenoxy)-5-formylbenzonitrile

The title compound was prepared by a procedure similar to that describedfor D80 starting from 2-fluoro-5-formylbenzonitrile and 3-fluorophenol.

LC-MS (ESI): m/z 242 [M+H]⁺; 3.09 min (ret time)

D146 2-(3-Fluorophenoxy)-5-(hydroxymethyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor D79 starting from 2-(3-fluorophenoxy)-5-formylbenzonitrile.

LC-MS (ESI): m/z 244 [M+H]⁺; 2.78 min (ret time)

D147 2-(3,5-Difluorophenoxy)-5-formylbenzonitrile

The title compound was prepared by a procedure similar to that describedfor D80 starting from 2-fluoro-5-formylbenzonitrile and 3-fluorophenol.

LC-MS (ESI): m/z 260 [M+H]⁺; 3.13 min (ret time)

D148 2-(3,5-Difluorophenoxy)-5-(hydroxymethyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor D79 starting from 2-(3,5-difluorophenoxy)-5-formylbenzonitrile.

LC-MS (ESI): m/z 262 [M+H]⁺; 2.83 min (ret time)

D149 2-(Trifluoromethyl)pyrimidin-5-ol

To a solution of 1,3-diaminopropan-2-ol (3.60 g, 40.0 mmol) in xylene(30 mL) was added ethyl 2,2,2-trifluoroacetate (5.70 g, 40.8 mmol) andstirred at 130° C. overnight, then the mixture was cooled to roomtemperature and concentrated. The residue was dissolved in nitrobenzene(60 mL), and then MeONa (8.50 g, 157.0 mmol) was added. The reactionmixture was stirred at 120° C. for 1 h. Then the mixture was cooled toroom temperature and poured into water (200 mL), extracted with EA (200mL). The aqueous phase adjust to pH=4 with 6M HCl and extracted with EA(200 mL), dried over Na₂SO₄, filtered and concentrated to give a crudeproduct. The residue was purified by column chromatography on silica geleluting with DCM/MeOH (30:1) to give the title compound (1.80 g, 28%yield) as a yellow solid.

¹H NMR (300 MHz, DMSO-d₆): δ 11.48 (br s, 1H), 8.52 (s, 2H).

D150 3,5-Difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzaldehyde

To a solution of 2-(trifluoromethyl)pyrimidin-5-ol (1.61 g, 10.0 mmol)in DMF (30 mL) was added 3,4,5-trifluorobenzaldehyde (1.60 g, 10.0 mmol)and K₂CO₃ (4.14 g, 30.0 mmol). The reaction mixture was stirred at 80°C. overnight. Then the mixture was cooled to room temperature and pouredinto water (150 mL), extracted with EA (2×100 mL), dried over Na₂SO₄,filtered and concentrated to give a crude product. The residue waspurified by column chromatography on silica gel eluting with PE/EA(10:1) to give the title compound (2.10 g, 69% yield) as yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 9.97 (s, 1H), 8.59 (s, 2H), 7.65 (d, J=7.2Hz, 2H).

D151(3,5-Difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol

To a solution of3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzaldehyde(2.10 g, 6.9 mmol) in MeOH (20 mL) was added in portions NaBH₄ (262 mg,6.9 mmol) at 0° C. Then the reaction mixture was stirred at roomtemperature for 0.5 h and poured into water (50 mL), extracted with EA(2×30 mL), dried over Na₂SO₄, filtered and concentrated to give a crudeproduct. The residue was purified by column chromatography on silica geleluting with PE/EA (10:1) to give the title compound (957 mg, 45% yield)as a yellow solid.

¹H NMR (300 MHz, CDCl₃): δ 8.55 (s, 2H), 7.13 (d, J=8.1 Hz, 2H), 4.76(d, J=5.7 Hz, 2H).

D152 Methyl 3,5-difluoro-4-((3-hydroxycyclohexyl)oxy)benzoate

To a solution of methyl 3,5-difluoro-4-hydroxybenzoate (376 mg, 2 mmol),cyclohexane-1,3-diol (464 mg, 4 mmol) and PPh₃ (1.05 g, 4 mmol) in THF(15 mL) was added DIAD (808 mg, 4 mmol) dropwise at 0° C. under N₂. Thereaction was slowly warmed up to room temperature and stirred for 30min. The mixture was concentrated, and the residue was triturated withTBME, and filtered. The filtrate was concentrated and purified withsilica gel column (TBME/EA=3/1˜1/1) to give the title compound (500 mg,yield 87%) as yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 7.62-7.54 (m, 2H), 4.32-4.22 (m, 1H), 3.91(s, 3H), 3.75-3.69 (m, 1H), 1.97-1.46 (m, 8H).

D153 Methyl 3,5-difluoro-4-((3-oxocyclohexyl)oxy)benzoate

To a solution of methyl3,5-difluoro-4-((3-hydroxycyclohexyl)oxy)benzoate (500 mg, 1.75 mmol) inDCM (10 mL) was added DMP (964 mg, 2.27 mmol) at room temperature andthe reaction was stirred at room temperature overnight. The reaction wasdiluted with TBME/PE (1:1, 30 mL), then filtered. The filtrate waswashed with water and brine, dried, concentrated and purified withsilica gel column (PE/EA=10/1) to give the title compound (300 mg, yield60%) as colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 7.62-7.55 (m, 2H), 4.78-4.71 (m, 1H), 3.90(s, 3H), 2.71 (d, J=5.1 Hz, 2H), 2.46-2.36 (m, 2H), 2.25-2.13 (m, 1H),2.09-2.03 (m, 2H), 1.82-1.72 (m, 1H).

D154 Methyl 4-((3,3-difluorocyclohexyl)oxy)-3,5-difluorobenzoate

To a solution of methyl 3,5-difluoro-4-((3-oxocyclohexyl)oxy)benzoate(800 mg, 2.8 mmol), in DCM (10 mL) was added DAST (1.36 g, 8.4 mmol) atroom temperature and the reaction was stirred at room temperatureovernight. The reaction was poured into sat. NaHCO₃ (80 mL) withstirring at RT, then extracted with DCM (40 mL×2). The combined organiclayer was dried, concentrated and purified with silica gel column(PE/EA=20/1) to give the title compound (820 mg, yield 95%) as colorlessoil.

¹H NMR (300 MHz, CDCl₃): δ 7.64-7.55 (m, 2H), 4.43-4.37 (m, 1H), 3.91(s, 3H), 2.60-2.49 (m, 1H), 3.13-1.49 (m, 7H).

D155 (4-((3,3-Difluorocyclohexyl)oxy)-3,5-difluorophenyl)methanol

To a solution of methyl4-((3,3-difluorocyclohexyl)oxy)-3,5-difluorobenzoate (1.73 g, 5.7 mmol)in THF (40 mL) was added LiAlH₄ (215 mg, 5.7 mmol) at 0° C. The mixturewas stirred at room temperature for 1 hour. MeOH (10 mL) was added toquench the reaction. Potassium sodium tartrated (sat. 10 mL) was added,the mixture was stirred at room temperature for 20 min. The mixture wasfiltered and the filtrate was evaporated. The residue was purified byflash chromatography on silica gel (PE/EA=40/1-10/1) to give the titlecompound (722 mg, yield 46%) as yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 6.94-6.91 (m, 2H), 4.63 (s, 2H), 4.22-4.20(m, 1H), 2.56-2.52 (m, 1H), 2.11-1.51 (m, 8H).

D156 Methyl 4-((3-(benzyloxy)cyclopentyl)oxy)-3,5-difluorobenzoate

To a solution of methyl 3,5-difluoro-4-hydroxybenzoate (376 mg, 2 mmol),3-(benzyloxy)cyclopentanol (420 mg, 2.2 mmol) and PPh₃ (1.05 g, 4 mmol)in THF (15 mL) was added DIAD (808 mg, 4 mmol) dropwise at 0° C. underN₂. The reaction was stirred at RT for 2 hours. The mixture wasconcentrated and the residue was triturated with TBME/PE (1:3, 30 mL),filtered. The filtrate was concentrated and purified with silica gelcolumn (PE/EA=30/1˜20/1) to give the title compound (600 mg, yield 83%)as yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 7.62-7.53 (m, 2H), 7.37-7.25 (m, 5H),4.94-4.90 (m, 1H), 4.52 (s, 2H), 4.05-4.01 (m, 1H), 3.90 (s, 3H),2.33-2.23 (m, 1H), 2.12-1.80 (m, 5H).

D157 Methyl 3,5-difluoro-4-((3-hydroxycyclopentyl)oxy)benzoate

A mixture of methyl4-((3-(benzyloxy)cyclopentyl)oxy)-3,5-difluorobenzoate (3.9 g, 10.8mmol) and 10% Pd/C (wet, 1.3 g) in MeOH (30 mL) was stirred at 50° C.under H₂ (50 psi) for 2 days. The mixture was filtered, concentrated andpurified with silica gel column (PE/EA=50/1˜10/1) to give the titlecompound (1.51 g, yield 52%) as colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 7.65-7.57 (m, 2H), 5.10-5.07 (m, 1H),4.61-4.38 (m, 1H), 3.91 (s, 3H), 2.24-1.80 (m, 6H).

D158 Methyl 3,5-difluoro-4-((3-oxocyclopentyl)oxy)benzoate

To a solution of methyl3,5-difluoro-4-((3-hydroxycyclopentyl)oxy)benzoate (1.51 g, 5.6 mmol) inDCM (30 mL) was added DMP (3.06 g, 7.2 mmol) at RT and the reaction wasthen stirred at RT for 4 hours. The reaction was diluted with water (50mL) and filtered. The filtrate was extracted with DCM (50 mL×2), driedover Na₂SO₄, filtered, concentrated and purified by silica gel column(PE/EA=5/1) to give the title compound (1.48 g, yield 99%) as yellowoil.

¹H NMR (300 MHz, CDCl₃): δ 7.62-7.59 (m, 2H), 5.22-5.21 (m, 1H), 3.91(s, 3H), 2.62-2.49 (m, 3H), 2.35-2.30 (m, 2H), 2.18-2.09 (m, 1H).

D159 Methyl 4-((3,3-difluorocyclopentyl)oxy)-3,5-difluorobenzoate

To a solution of methyl 3,5-difluoro-4-((3-oxocyclopentyl)oxy)benzoate(2.24 g, 8.3 mmol), in DCM (40 mL) was added DAST (4.00 g, 24.9 mmol) atRT, the reaction was stirred at RT overnight. The reaction was pouredinto sat. NaHCO₃ (320 mL) with stirring at RT, then extracted with DCM(50 mL×2). The combined DCM was dried over Na₂SO₄, concentrated andpurified with silica gel column (PE/EA=20/1) to give the title compound(1.02 g, yield 42%) as yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 7.61-7.59 (m, 2H), 4.96 (br s, 1H), 3.91 (s,3H), 2.57-2.43 (m, 3H), 2.18-2.03 (m, 3H).

D160 (4-((3,3-Difluorocyclopentyl)oxy)-3,5-difluorophenyl)methanol

To a solution of methyl4-((3,3-difluorocyclopentyl)oxy)-3,5-difluorobenzoate (1.02 g, 3.5 mmol)in dry THF (30 mL) was added LiAlH₄ (133 mg, 3.5 mmol) in portions at 0°C. under N₂. The reaction mixture was stirred at RT for 0.5 hours, thenadded drop wise MeOH (5 mL) at room temperature and stirred for 10 min,added sat. Potassium sodium tartrate tetrahydrate (aq, 15 mL) werestirred for 1 h, added Na₂SO₄ and stirred for 1 hour. The reactionmixture was filtered and concentrated under reduced pressure to give theresidue. The residue was purified by silica gel column (PE/EA=5:1) togive the title compound (808 mg, yield 88%) as yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 6.96-6.89 (m, 2H), 4.83-4.82 (m, 1H),4.64-4.62 (m, 2H), 2.51-2.41 (m, 3H), 2.16-2.00 (m, 3H), 1.81-1.77 (m,1H).

D161 4-((1-Benzhydrylazetidin-3-yl)oxy)-3,5-difluorobenzoic Acid

To a solution of 3,4,5-trifluorobenzoic acid (50 g, 284 mmol) and1-benzhydrylazetidin-3-ol (68 g, 284 mmol) in DMF (1 L) was added NaH(60% in mineral oil, 34 g, 852 mmol) at 0° C. The mixture was stirred atroom temperature for 16 hrs and then stirred at 50° C. for 3 hrs. Themixture was poured into ice-water. The mixture was acidified with conc.HCl to pH=3, then filtered to give a solid. The solid was trituratedwith PE (300 mL) and filtered to give the title compound (88 g, yield79%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 7.66-7.26 (m, 12H), 5.21-4.99 (m, 1H),3.81-3.31 (m, 4H).

D162 Methyl 4-((1-benzhydrylazetidin-3-yl)oxy)-3,5-difluorobenzoate

A mixture of 4-((1-benzhydrylazetidin-3-yl)oxy)-3,5-difluorobenzoic acid(10 g, 25.3 mmol) and conc H₂SO₄ (1 mL) in MeOH (100 mL) was stirred at80° C. overnight. The mixture was concentrated and poured into ice-water(50 mL). The aqueous solution was extracted with DCM (100 mL×2), driedover Na₂SO₄, concentrated to give the crude title compound (11 g, yield100%) as a yellow solid.

D163 Methyl 4-(azetidin-3-yloxy)-3,5-difluorobenzoate

A mixture of methyl4-((1-benzhydrylazetidin-3-yl)oxy)-3,5-difluorobenzoate (35 g, 85 mmol),20% Pd(OH)₂/C (6 g) and AcOH (6 mL) in MeOH (1.0 L) was stirred at 70°C. under H₂ (50 Psi) overnight. The mixture was filtered, concentratedand the residue was purified by flash chromatograph on silica gel(DCM/MeOH=30/1 to 10/1) to give the title compound (38 g, yield 91%) asa yellow solid.

¹H NMR (300 MHz, DMSO-d₆): δ 7.64-7.55 (m, 2H), 5.14-5.10 (m, 1H),4.18-4.06 (m, 4H), 3.92 (s, 3H).

D164 Methyl3,5-difluoro-4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)oxy)benzoate

A solution of methyl 4-(azetidin-3-yloxy)-3,5-difluorobenzoate (1.0 g,4.1 mmol), 1,1,1-trifluoro-3-iodopropane (922 mg, 4.1 mmol) and DIEA(1.06 g, 8.2 mmol) in acetonitrile (20 mL) was heated to reflux andstirred for 4 hours. The solution was evaporated and purified by flashchromatograph on silica gel (PE/EA=20/1) to give the title compound (620mg, yield 45%) as yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 7.62-7.55 (m, 2H), 4.91-4.87 (m, 1H), 3.91(s, 3H), 3.80-3.75 (m, 2H), 3.27-3.22 (m, 2H), 2.78-2.73 (m, 2H),2.26-2.13 (m, 2H).

D165(3,5-Difluoro-4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)oxy)phenyl)methanol

To a solution of methyl3,5-difluoro-4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)oxy)benzoate(620 mg, 1.8 mmol) in THF (30 mL) was added LiAlH₄ (70 mg, 1.8 mmol) at0° C. Then the mixture was stirred at 0° C. for 30 min. The mixture wasquenched with Na₂SO₄.10H₂O (2.0 g). The mixture was filtered andevaporated to give the title compound (480 mg, yield 81%) as yellow oil.

LC-MS (ESI): m/z 312 [M+H]⁺; 3.65 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 6.94-6.91 (m, 2H), 4.75-4.71 (m, 1H), 4.62(s, 2H), 3.76-3.71 (m, 2H), 3.2-3.19 (m, 2H), 2.77-2.72 (m, 2H),2.22-2.12 (m, 2H).

D166 Methyl 4-((1-butylazetidin-3-yl)oxy)-3,5-difluorobenzoate

A mixture of methyl 4-(azetidin-3-yloxy)-3,5-difluorobenzoate (2.0 g,8.2 mmol), 1-bromobutane (1.4 g, 9.8 mmol) and DIEA (1.6 g, 12.3 mmol)in CH₃CN (20 mL) was stirred at 95° C. overnight. The reaction mixturewas concentrated and purified by flash chromatography on silica gel(PE:EA=10:1) to give the title compound (850 mg, 34%) as a yellow oil.

LC-MS (ESI): m/z 300 [M+H]⁺; 2.88 min (ret time).

D167 (4-((1-Butylazetidin-3-yl)oxy)-3,5-difluorophenyl)methanol

To a solution of methyl4-((1-butylazetidin-3-yl)oxy)-3,5-difluorobenzoate (1.1 g, 3.7 mmol) inTHF (20 mL) was added LiAlH₄ (141 mg, 3.7 mmol) at 0° C. The mixture wasstirred at 0° C. for 30 min. The mixture was quenched with MeOH (5 mL)and sat potassium sodium tartrate (10 mL). The mixture was stirred atroom temperature for 30 min. Na₂SO₄ (15 g) was added, filtered andconcentrated to give title compound (630 mg, 63%) as yellow oil.

LC-MS (ESI): m/z 272 [M+H]⁺; 2.43 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 6.96-6.90 (m, 2H), 4.60 (s, 2H), 4.50-4.46(m, 1H), 3.67-3.62 (m, 2H), 3.15-3.10 (m, 2H), 2.52-2.47 (m, 2H),1.39-1.29 (m, 4H), 0.94-0.90 (m, 2H

D168 Ethyl 3-(4-bromo-2,6-difluorophenyl)acrylate

To a solution of 4-bromo-2,6-difluorobenzaldehyde (25.0 g, 113.1 mmol)in EA (113 mL) was added PPh₃ (41.49 g, 158.4 mmol), sat. NaHCO₃ (226mL) and ethyl 2-bromoacetate (28.34 g, 169.7 mmol). The reaction mixturewas stirred vigorously at room temperature for 3 hours. The reactionmixture was diluted with water (150 mL) and extracted with EA (300 mL),the organic layers was washed with water (250 mL) and brine (250 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure to give the residue. The residue was purified by silica gelcolumn (PE/EA=40:1) to give the title compound (33.25 g, yield 100%) asa white solid.

¹H NMR (300 MHz, CDCl₃): δ 7.67 (d, J=16.5 Hz, 1H), 7.14 (d, J=7.8 Hz,2H), 6.71 (d, J=16.5 Hz, 1H), 4.27 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 HZ,3H).

D169 3-(4-Bromo-2,6-difluorophenyl)propan-1-ol

To a solution of ethyl 3-(4-bromo-2,6-difluorophenyl)acrylate (17.46 g,60.0 mmol) in dry THF (500 mL) was added LiBH₄ (6.06 g, 300.0 mmol) at0° C. under N₂. The reaction mixture was stirred at RT overnight, thenadded drop wise sat.NH₄Cl (aq, 200 mL) at room temperature, added water(200 mL) and extracted with EA (400 mL), washed with brine (200 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive the residue. The residue was purified by silica gel column(PE/EA=10:1) to give the title compound (8.10 g, yield 54%) as colorlessoil.

¹H NMR (300 MHz, CDCl₃): δ 7.06-7.02 (m, 2H), 3.68-3.63 (m, 2H),2.75-2.60 (m, 2H), 1.87-1.80 (m, 2H).

D170 Methyl 3,5-difluoro-4-(3-hydroxypropyl)benzoate

A mixture of 3-(4-bromo-2,6-difluorophenyl)propan-1-ol (8.10 g, 32.3mmol), Pd(dppf)Cl₂ (2.63 g, 3.2 mmol) and TEA (6.52 g, 64.5 mmol) inMeOH (100 mL) was stirred at 100° C. under CO (2 MPa) for 24 hours. Thereaction mixture was cooled to room temperature, filtered andconcentrated. The residue dissolved in EA (400 mL), washed with water(200 mL) and brine (200 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give the residue. The residue waspurified by silica gel column (PE/EA=5:1) to give the title compound(2.83 g, yield 38%) as red oil.

¹H NMR (300 MHz, CDCl₃): δ 7.53 (d, J=8.1 Hz, 2H), 3.92 (s, 3H), 3.67(t, J=6.6 Hz, 2H), 2.81 (t, J=7.5 Hz, 2H), 1.91-1.84 (m, 2H), 1.51 (brs, 1H)

D171 Methyl 3,5-difluoro-4-(3-fluoropropyl)benzoate

To a solution of methyl 3,5-difluoro-4-(3-hydroxypropyl)benzoate (1.04g, 4.5 mmol) in DCM (20 mL) was added dropwise DAST (1.09 g, 6.8 mmol)at 0° C. The reaction mixture was stirred at RT for 1.5 hours. Thereaction mixture was quenched with sat. NaHCO₃ (aq, 40 mL), extractedwith DCM (40 mL) and dried over Na₂SO₄. Filtered and concentrated togive the residue. The residue was purified by silica gel column(PE/EA=25:1) to give the title compound (470 mg, yield 45%) as yellowoil.

¹H NMR (300 MHz, CDCl₃): δ 7.53 (d, J=8.1 Hz, 2H), 4.55 (t, J=6.0 Hz,1H), 4.39 (t, J=6.0 Hz, 1H), 3.91 (s, 3H), 2.85 (t, J=7.5 Hz, 2H),2.06-1.93 (m, 2H).

D172 (3,5-Difluoro-4-(3-fluoropropyl)phenyl)methanol

To a solution of methyl 3,5-difluoro-4-(3-fluoropropyl)benzoate (470 mg,2.0 mmol) in dry THF (20 mL) was added LiAlH₄ (77 mg, 2.0 mmol) inportions at 0° C. under N₂. The reaction mixture was stirred at RT for0.5 hours, then added drop wise MeOH (10 mL) at room temperature andstirred for 10 min, added sat. Potassium sodium tartrate (aq, 15 mL)stirred 0.5 hours, added Na₂SO₄ and stirred 0.5 hours, filtered andconcentrated under reduced pressure to give the residue. The residue waspurified by silica gel column (PE/EA=10:1) to give the title compound(356 mg, yield 86%) as a yellow solid.

¹H NMR (300 MHz, CDCl₃): δ 6.88 (d, J=7.8 Hz, 2H), 4.65 (s, 2H), 4.54(t, J=6.0 Hz, 1H), 4.38 (t, J=6.0 Hz, 1H), 2.79 (t, J=7.5 Hz, 2H),2.04-1.91 (m, 2H), 1.74 (br s, 1H).

D173 3,5-Difluoro-4-((2-methylpyridin-4-yl)oxy)benzaldehyde

To a solution of 3,4,5-trifluorobenzaldehyde (2.9 g, 18 mmol)2-methylpyridin-4-ol (2.0 g, 18 mmol) in dry DMF (50 mL) was added K₂CO₃(7.6 g, 55 mmol) at 80° C. The reaction mixture was stirred at 80° C.overnight. The reaction mixture was concentrated and the residue wasdissolved with water (100 mL), extracted with EA (100 mL×3). Thecombined organic layers were dried over anhydrous Na₂SO₄, concentratedunder reduced pressure. The residue was purified by columnchromatography on silica gel eluting with PE/EA (4:1) to give the titlecompound (1.5 g, 34% yield) as colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 9.95 (t, J=1.8 Hz, 1H), 8.40 (d, J=5.7 Hz,1H), 7.63-7.57 (m, 2H), 6.70-6.67 (m, 2H), 2.53 (s, 3H).

D174 (3,5-Difluoro-4-((2-methylpyridin-4-yI)oxy)phenyl)methanol

To a solution of 3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzaldehyde(1.5 g, 6.0 mmol) in MeOH (50 mL) was added NaBH₄ (228 mg, 6.0 mmol) at0° C. The reaction mixture was stirred at RT for 2 h. The reactionmixture was concentrated and the residue was dissolved with water (100mL), extracted with EA (100 mL×3). The combined organic layers weredried over anhydrous Na₂SO₄, and concentrated under reduced pressure.The residue was purified by prep-HPLC to give the title compound (1.45g, 97% yield) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 8.31 (d, J=5.7 Hz, 1H), 7.10-7.05 (m, 2H),4.73 (d, J=5.7 Hz, 2H), 2.50 (s, 3H), 2.17 (t, J=0.9 Hz, 1H). LCMS:rt=3.260 min, [M+H]⁺=252.

D175 2-(4-Fluoro-3-(trifluoromethyl)phenoxy)-5-formylbenzonitrile

To the solution of 2-fluoro-5-formylbenzonitrile (1.5 g, 10.06 mmol) and4-fluoro-3-(trifluoromethyl)phenol (1.812 g, 10.06 mmol) in acetonitrile(18 ml), was added K₂CO₃ (1.807 g, 13.08 mmol). The reaction mixture wassealed and heated in Biotage Initiator using initial normal to 130° C.for 1 h. After cooling the reaction, the reaction mixture was filtratedand evaporated invacuo to give crude product2-(4-fluoro-3-(trifluoromethyl)phenoxy)-5-formylbenzonitrile (3 g, 9.70mmol, 96% yield) as a white solid.

LCMS: Rt=3.38 min, [M−H]⁺=310.

D1762-(4-Fluoro-3-(trifluoromethyl)phenoxy)-5-(hydroxymethyl)benzonitrile

To the solution of2-(4-fluoro-3-(trifluoromethyl)phenoxy)-5-formylbenzonitrile (3 g, 9.70mmol) in methanol (30 ml), was added NaBH₄ (0.551 g, 14.55 mmol). Thereaction mixture was stirred at rt for 30 min, then quenched by waterand extracted with EA twice. The organic phase was washed with brine,dried over Na₂SO₄ and evaporated in vacuo to give crude product2-(4-fluoro-3-(trifluoromethyl)phenoxy)-5-(hydroxymethyl)benzonitrile(2.3 g, 7.39 mmol, 76% yield) as white solid

LCMS: Rt=1.70 min, [M−H]⁺=310.

D177 4-Bromo-1-(1-ethoxyethyl)-1H-pyrazole

To a solution of 4-bromo-1H-pyrazole (6.0 g, 41 mmol), ethoxyethene (3.5g, 49 mmol) in THF (60 mL) was added HCl in dioxane (sat. 1 mL). Themixture was stirred at room temperature for 3 hrs. NaHCO₃ (sat. 5 mL)was added to quench the reaction. The mixture was extracted DCM (100mL×3), washed with water (100 mL×3), brine, dried over anhydrous Na₂SO₄and concentrated under reduced pressure to give the title compound (10g, 100% yield) as grey oil.

¹H NMR (300 MHz, CDCl₃): δ 7.59 (d, J=0.6 Hz, 1H), 7.44 (d, J=0.6 Hz,1H), 5.45 (q, J=6.0 Hz, 1H), 3.47-3.29 (m, 2H), 1.62 (d, J=6.0 Hz, 3H),1.13 (t, J=6.9 Hz, 3H).

D1781-(1-Ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

To a solution of 4-bromo-1-(1-ethoxyethyl)-1H-pyrazole (6.2 g, 28 mmol)in THF (100 mL) was added i-PrMgCl (2 mmol/L, 25 mL) at room temperaturefor 3 hrs. 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.6 g,67.9 mmol) was added at room temperature for 3 h. NH₄Cl (sat. 20 mL) wasadded to quench the reaction. The mixture was extracted PE:EtOAc=(200mL:200 mL×3), washed with water (300 mL×3), brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure to give the titlecompound (7 g, 100% yield) as yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 7.89 (s, 1H), 7.78 (s, 1H), 5.54-5.52 (m,1H), 3.46-3.31 (m, 3H), 1.70-1.64 (m, 3H), 1.36 (s, 9H), 1.21-1.10 (m,3H).

D179 1-(1-Ethoxyethyl)-1H-pyrazol-4-ol

To a solution of1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(7.0 g, 27 mmol) in THF (100 mL) was added NaOH (2 mmol/L, 16 mL), H₂O₂(30%, 2.5 mL, 32 mL) at room temperature for 2 hrs. HCl (2 mol/L, 20 mL)was added to adjust pH=6-7. The mixture was extracted DCM (200 mL×3),washed with water (100 mL×3), brine, dried over anhydrous Na₂SO₄ andconcentrated under pressure concentrated and purified by columnchromatography on silica gel eluting with PE/EA (4:1˜2:1) to give thetitle compound (4.2 g, 100% yield) as yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 7.23 (d, J=0.9 Hz, 1H), 7.17 (d, J=0.9 Hz,1H), 5.34 (q, J=6.0 Hz, 1H), 3.44-3.27 (m, 2H), 1.58 (d, J=6.0 Hz, 3H),1.11 (t, J=7.2 Hz, 3H).

D180 4-((1-(1-Ethoxyethyl)-1H-pyrazol-4-yl)oxy)-3,5-difluorobenzaldehyde

A mixture of 1-(1-ethoxyethyl)-1H-pyrazol-4-ol (3.0 g, 19 mmol),3,4,5-trifluorobenzaldehyde (3.0 g, 19 mmol), K₂CO₃ (8.0 g, 58 mmol) inDMF (20 mL) was stirred at 60° C. for 2 hrs. The mixture was washed withwater (200 mL×3), brine, extracted DCM (200 mL×3), dried over anhydrousNa₂SO₄ and concentrated under pressure concentrated and purified bycolumn chromatography on silica gel eluting with PE/EA (4:1˜2:1) to givethe title compound (2.1 g, 37% yield) as yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 9.89 (t, J=1.8 Hz, 1H), 7.55-7.53 (m, 2H),7.44 (s, 1H), 7.32 (s, 1H), 5.40 (q, J=6.0 Hz, 1H), 3.47-3.33 (m, 2H),1.61 (d, J=6.0 Hz, 3H), 1.13 (t, J=7.2 Hz, 3H).

D181 4-((1H-Pyrazol-4-yl)oxy)-3,5-difluorobenzaldehyde

A mixture of4-((1-(1-ethoxyethyl)-1H-pyrazol-4-yl)oxy)-3,5-difluorobenzaldehyde (2.1g, 7.1 mmol) in HCl (2 mol/L): HCl in dioxane (sat.)=15 mL: 15 mL wasstirred at room temperature for 1 h. NaOH (2 mol/L, 50 mL) was added toadjust pH=6-7. The mixture was extracted EtOAc (200 mL×3), washed withwater (200 mL×3), brine, dried over anhydrous Na₂SO₄ and concentratedunder pressure concentrated and purified by column chromatography onsilica gel eluting with PE/EA (1:1) to give the title compound (1.5 g,94% yield) as yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 9.89 (t, J=1.8 Hz, 1H), 7.53-7.45 (m, 4H).

D182 3,5-Difluoro-4-((1-propyl-1H-pyrazol-4-yl)oxy)benzaldehyde

A mixture of 4-((1H-pyrazol-4-yl)oxy)-3,5-difluorobenzaldehyde (1.5 g,6.7 mmol), 1-bromopropane (1.65 g, 13.4 mmol), K₂CO₃ (2.78 g, 20.1 mmol)in DMF (25 mL) was stirred at 30° C. overnight. The mixture was washedwith water (100 mL×3), brine, extracted EtOAc (100 mL×3), dried overanhydrous Na₂SO₄ and concentrated under pressure concentrated andpurified by column chromatography on silica gel eluting with PE/EA (4:1)to give the title compound (1.2 g, 80% yield) as yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 9.89-9.88 (m, 1H), 7.54-7.47 (m, 2H),7.30-7.27 (m, 2H), 3.99 (t, J=6.9 Hz, 2H), 1.91-1.76 (m, 2H), 0.91 (t,J=4.2 Hz, 3H).

D183 (3,5-Difluoro-4-((1-propyl-1H-pyrazol-4-yl)oxy)phenyl)methanol

To a solution of3,5-difluoro-4-((1-propyl-1H-pyrazol-4-yl)oxy)benzaldehyde (1.2 g, 4.51mmol) in methanol (20 mL) was added NaBH₄ (171 mg, 45.1 mmol) at RT for1 h. NaOH (sat. 1 mL) was added to quench the reaction. The mixture wasconcentrated with silica gel and purified by column chromatography onsilica gel eluting with PE/EA (4:1) to give the title compound (1.2 g,99% yield) as a white solid.

LCMS: Rt=3.505 min, [M+H]⁺=269.

¹H NMR (300 MHz, CDCl₃) δ 7.25-7.20 (m, 2H), 6.98 (d, J=3.6 Hz, 2H),4.66 (d, J=3.6 Hz, 2H), 3.96 (t, J=3.6 Hz, 2H), 2.10 (t, J=6.0 Hz, 1H),1.86-1.79 (m, 2H), 0.89 (t, J=7.2 Hz, 3H).

D184 3,5-Difluoro-4-((6-methylpyridin-3-yl)oxy)benzaldehyde

To a solution of 3,4,5-trifluorobenzaldehyde (2.9 g, 18 mmol),6-methylpyridin-3-ol (2.0 g, 18 mmol) in dry DMF (50 mL) was added K₂CO₃(7.6 g, 55 mmol) at 50° C. The reaction mixture was stirred at 50° C.overnight, and then concentrated. The residue was dissolved with water(100 mL), extracted with EA (100 mL×3). The combined organic layers wasdried over anhydrous Na₂SO₄, concentrated under reduced pressure andpurified by column chromatography on silica gel eluting with PE/EA (4:1)to give the title compound (4.0 g, 89% yield) as colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 9.91 (t, J=1.8 Hz, 1H), 8.27 (d, J=3.0 Hz,1H), 7.59-7.51 (m, 2H), 7.19-7.09 (m, 2H), 2.53 (s, 3H).

D185 (3,5-Difluoro-4-((6-methylpyridin-3-yl)oxy)phenyl)methanol

To a solution of 3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzaldehyde(4.0 g, 16 mmol) in MeOH (50 mL) was added NaBH₄ (610 mg, 16.1 mmol) at0° C. The reaction mixture was stirred at RT for 2 h. The reactionmixture was concentrated and the residue was dissolved with water (100mL), extracted with EA (100 mL×3). The combined organic layers was driedover anhydrous Na₂SO₄, concentrated under reduced pressure and purifiedby prep-HPLC to give the title compound (3.76 g, 94% yield) as a whitesolid.

¹H NMR (300 MHz, CDCl₃): δ 8.23 (d, J=2.7 Hz, 1H), 7.26-7.01 (m, 4H),4.71 (d, J=5.7 Hz, 2H), 2.51 (s, 3H), 2.33 (t, J=6.0 Hz, 1H).

D1864-((1-(Bromodifluoromethyl-1H-pyrazol-4-yl)oxy)-3,5-difluorobenzaldehyde

A mixture of 4-((1H-pyrazol-4-yl)oxy)-3,5-difluorobenzaldehyde, CF₂Br₂(3 ml), K₂CO₃ (4.25 g, 30.9 mmol) in DMF (35 mL) was stirred at roomtemperature overnight. The mixture was filtrated, concentrated andpurified by column chromatography on silica gel eluting with PE/EA (9:1)to give the title compound (600 mg, 17% yield) as yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 9.91 (t, J=1.8 Hz, 1H), 7.67-7.54 (m, 4H).

D1873,5-Difluoro-4-((1-(trifluoromethyl)-1H-pyrazol-4-yl)oxy)benzaldehyde

To a solution of4-((1-(bromodifluoromethyl)-1H-pyrazol-4-yl)oxy)-3,5-difluorobenzaldehyde(600 mg, 1.61 mmol), HgO (1.1 g, 5.07 mol) in isopropyl ether (20 mL)was added HF-Pyridine solution (2 mL) at room temperature overnight.Sat. KF solution (1 mL) was added to quench the reaction. The reactionmixture was concentrated and the residue was dissolved with water (40mL), and extracted with EA (20 mL×3). The combined organic layers wasdried over anhydrous Na₂SO₄, concentrated and purified by columnchromatography on silica gel eluting with PE/EA (4:1) to give the titlecompound (450 mg, 75% yield) as yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 9.92-9.90 (m, 1H), 7.68-7.52 (m, 4H).

D188(3,5-Difluoro-4-((1-(trifluoromethyl)-1H-pyrazol-4-yl)oxy)phenyl)methanol

To a solution of3,5-difluoro-4-((1-(trifluoromethyl)-1H-pyrazol-4-yl)oxy)benzaldehyde(420 mg, 1.44 mmol) in methanol (20 mL) was added NaBH₄ (55 mg, 1.44mmol) at room temperature for 1 hour. NaOH (sat. 1 mL) was added toquench the reaction. The mixture was concentrated with silica gel andpurified by column chromatography on silica gel eluting with PE/EA (4:1)to give the title compound (160 mg, 40% yield) as yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 7.59-7.47 (m, 2H), 7.07-6.96 (m, 2H), 4.70(t, J=4.8 Hz, 2H), 2.50 (s, 1H). LCMS: Rt=3.822 min, [M+H]⁺=295.

D189 3,5-Difluoro-4-((2-methylpyrimidin-5-yl)oxy)benzaldehyde

To a solution of 2-methylpyrimidin-5-ol (4.5 g, 41 mmol) and3,4,5-trifluorobenzaldehyde (6.6 g, 41 mmol) in DMF (150 mL) was addedNaH (60% in mineral oil, 3.3 g, 82 mmol) at 0° C. The reaction mixturewas stirred at RT for 2 hrs. The reaction mixture was concentrated andthe residue was dissolved with water (100 mL), extracted with EA (200mL×3). The combined organic layers were washed with brine and dried overanhydrous Na₂SO₄, then filtered and concentrated under reduced pressure.The residue was purified by column chromatography on silica gel elutingwith (PE/EA=50/1) to give the title compound (5.6 g, 55% yield) as awhite solid.

¹H NMR (300 MHz, CDCl₃): δ 9.93 (t, J=1.8 Hz, 1H), 8.39 (s, 2H),7.61-7.58 (m, 2H), 2.73 (s, 3H).

D190 (3,5-Difluoro-4-((2-methylpyrimidin-5-yl)oxy)phenyl)methanol

To a solution of3,5-difluoro-4-((5-methylpyrimidin-2-yl)oxy)benzaldehyde (4.0 g, 16mmol) in methanol (100 mL) was added NaBH₄ (1.2 g, 32 mmol) in portionsat 0° C. The reaction mixture was stirred at RT for 2 hrs. Then H₂O (5mL) was added to quench the reaction and the solution was concentrated.The residue was purified by column chromatography on silica gel elutingwith PE/EA=5/1 to give the title compound (2.6 g, 66%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 8.34 (s, 2H), 7.06 (d, J=8.4 Hz, 2H), 4.72(d, J=5.7 Hz, 2H), 2.71 (s, 3H), 1.97 (t, J=5.7 Hz, 1H).

D191 3-Hydroxy-3-phenylcyclobutanecarboxylic Acid

To a solution of 3-oxocyclobutanecarboxylic acid (100 g, 0.876 mol) indry THF (1200 mL) was added PhMgBr (2.9 M, 604 mL, 1.752 mol) drop wiseover 6 hrs at room temperature under N₂. Then saturated aq. NH₄Cl (1200mL) was added and the mixture was acidified with 12M conc. HCl to pH=3.The mixture was filtered and the solution was extracted with ether (2000mL×2). The combined organic layers were washed with brine (1000 mL×1),dried over Na₂SO₄, filtered and concentrated to give the title compound(168 g, 100%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 12.18 (s, 1H), 7.53-7.25 (m, 5H), 5.67 (s,1H), 2.70-2.46 (m, 5H).

D192 3-Chloro-3-phenylcyclobutanecarboxylic Acid

To a solution of 3-hydroxy-3-phenylcyclobutanecarboxylic acid (168.0 g,0.87 mol) in toluene (1500 mL) was added conc. HCl (1000 mL). Themixture was stirred at room temperature for 4 hrs. The organic phase wasseparated, washed with water (1000 mL, brine (1000 mL) and concentratedto give the title compound (152 g, 83%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 7.41-7.33 (m, 5H), 2.97-2.94 (m, 5H).

D193 Methyl 3-chloro-3-phenylcyclobutanecarboxylate

To a solution of 3-chloro-3-phenylcyclobutanecarboxylic acid (152 g,0.72 mol) and K₂CO₃ (219 g, 1.58 mol) in DMF (1500 mL) was added CH₃I(205 g, 1.44 mol). The mixture was stirred at room temperature forovernight. The result mixture was filtered and diluted with water (1500mL), extracted with EA (2500 mL). The organic phase was separated,washed with brine (2000 mL), dried over Na₂SO₄, filtered andconcentrated. The residue was purified by column chromatography onsilica gel eluting with PE/EtOAc (50:1˜30:1) to give the title compound(130 g, 80%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 7.48-7.30 (m, 5H), 3.70 (s, 3H), 3.30-2.90(m, 5H).

D194 Methyl 3-phenylbicyclo[1.1.0]butane-1-carboxylate

To a solution of NaHMDS (2.0 M, 350 mL, 0.70 mol) in THF (1000 mL) wasadded a solution of methyl 3-chloro-3-phenylcyclobutanecarboxylate(130.0 g, 0.58 mol) in THF (500 mL). The mixture was stirred at 70° C.for 5 hours. The mixture was cooled to room temperature. Then saturatedNH₄Cl (500 mL) was added and the mixture was filtered. The filtrate wasextracted with ether (2000 mL). The organic phase was washed with brine(2000 mL), dried over Na₂SO₄, filtered and concentrated. The residue waspurified by column chromatography on silica gel eluting with PE/EtOAc(50:1) to give a yellow solid and then recrystallization from hexane(500 mL) to give the title compound (67.4 g, 62%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 7.31-7.29 (m, 5H), 3.48 (s, 3H), 3.93-2.92(m, 2H), 1.61-1.60 (m, 2H).

D195 2,2-Dichloro-3-phenylbicyclo[1.1.1]pentane-1-carboxylic Acid

A mixture of methyl 3-phenylbicyclo[1.1.0]butane-1-carboxylate (67.4 g,0.358 mol) and diglyme (270 mL) in C₂Cl₄ (2700 mL) was heated to 120° C.Then, CCl₃COONa (249.0 g, 1.343 mol) was added in one portion. Themixture was heated to 140° C. for 3 hours and then cooled to roomtemperature, filtered through Celite and the filter cake was washed withDCM (300 mL×3). The filtrate was concentrated and purified by columnchromatography on silica gel eluting with PE/DCM (50:1˜20:1) to give thecrude product which was recrystallized from hexane to give the titlecompound (44.8 g, 46%) as a white solid.

¹H NMR (300 MHz, DMSO-d₆): δ 7.38-7.25 (m, 5H), 3.83 (s, 3H), 3.56-3.03(m, 2H), 1.95-1.80 (m, 2H).

D196 3-Phenylbicyclo[1.1.1]pentane-1-carboxylic Acid

A mixture of 2,2-dichloro-3-phenylbicyclo[1.1.1]pentane-1-carboxylicacid (10.0 g, 36.9 mmol), Bu₃SnH (48.3 g, 166 mmol) and AIBN (200 mg)was stirred under N₂ at 130° C. for 16 hours. After cooled to roomtemperature, AIBN (200 mg) was added and the mixture was stirred underN₂ at 130° C. for 20 hours. The mixture was cooled to room temperature,Bu₃SnH (5.68 g) and AIBN (200 mg) were added and stirred under N₂ at130° C. for 20 hours. The mixture was cooled to room temperature; AIBN(200 mg) was added and stirred under N₂ at 130° C. for 20 hours. Aftercooling, 10% NaOH (200 mL) was added. The mixture was heated at 100° C.for 2 hours. The mixture was cooled to room temperature, extracted withether (100 mL). The aqueous solution was acidified with conc. HCl topH=4, extracted with ether (200 mL×3). The organic layer was washed withbrine, dried over Na₂SO₄, filtered and concentrated to give the titlecompound (2.7 g, 30%) as a yellow solid.

¹H NMR (300 MHz, CDCl₃): δ 7.33-7.22 (m, 5H), 2.37 (s, 6H).

D197 Methyl 3-phenylbicyclo[1.1.1]pentane-1-carboxylate

To a mixture of 50% KOH (40 mL) in ether (40 mL) was addedamino-N-methyl-N-nitrosoamide (13.8 g) dropwise at 0° C. Ten minuteslater, the organic phase was separated, dried over KOH to give asolution of CH₂N₂ in ether (130 mL). To a solution of3-phenylbicyclo[1.1.1]pentane-1-carboxylic acid (2.70 g, 14.3 mol) inether (130 mL) was added the above solution of CH₂N₂ in ether (130 mL).The mixture was stirred at room temperature for 1 hour. 1 N HCl (100 mL)was added and stirred 10 min. The organic phase was separated, washedwith saturated NaHCO₃ (100 mL), brine (100 mL), dried over Na₂SO₄,filtered and concentrated to give the title compound (1.57 g, 54%) asbrown oil.

¹H NMR (300 MHz, CDCl₃): δ 7.45-7.21 (m, 5H), 3.73 (s, 3H), 2.33 (s,6H).

D198 3-(Methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic Acid

To a solution of methyl 3-phenylbicyclo[1.1.1]pentane-1-carboxylate(2.26 g, 11.2 mmol) in CCl₄ (68 mL), MeCN (68 mL) and H₂O (100 mL) wasadded NaIO₄ (43.1 g, 201.6 mmol) and RuCl₃.nH₂O (90 mg). The mixture wasstirred at room temperature for 1 day, extracted with DCM (100 mL×3).The organic phase was separated, washed with brine (200 mL), dried overNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography on silica gel eluting with DCM/MeOH (20:1) to give blackoil. The black oil was further purified by prep-TLC to give the titlecompound (220 mg, 11%) as a black solid.

¹H NMR (300 MHz, CDCl₃): δ 3.69 (s, 3H), 2.34 (s, 6H).

D199 Bicyclo[1.1.1]pentane-1,3-diyldimethanol

To a solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylicacid (220 mg, 1.29 mmol) in THF (5 mL) was added BH₃.THF (1.0 M, 2.6 mL,2.58 mmol) dropwise at 0° C. The mixture was stirred at room temperaturefor 2 hours and followed by addition of MeOH (5 mL). The mixture wasconcentrated to give the title compound (180 mg, 100%) as a black solid.

¹H NMR (300 MHz, CDCl₃): δ 3.62 (s, 4H), 1.64 (s, 6H).

D200(3-(((2-(Trifluoromethyl)pyridin-4-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)methanol

To a solution of bicyclo[1.1.1]pentane-1,3-diyldimethanol (90 mg, 0.63mmol) in DMF (2 mL) was added NaH (60% in mineral oil, 25 mg, 0.63 mmol)at 5° C. and stirred for 10 min, followed by addition of4-chloro-2-(trifluoromethyl)pyridine (102 mg, 0.56 mmol). The mixturewas stirred at 5° C. for overnight, diluted with water (5 mL) andextracted with EA (10 mL×3). The organic phases was washed with brine(20 mL), dried over Na₂SO₄, filtered and concentrated. The residue waspurified by prep-TLC (DCM/MeOH=20:1) to give the title compound (32 mg,24%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 8.51 (d, J=5.7 Hz, 1H), 7.26 (s, 1H), 7.18(d, J=2.4 Hz, 1H), 6.95-6.92 (m, 1H), 4.01 (s, 2H), 3.64 (s, 2H), 1.78(s, 6H).

D201 (4-Fluoro-3-(methylsulfonyl)phenyl)methanol

To a solution of 4-fluoro-3-(methylsulfonyl)benzaldehyde (150 mg, 0.742mmol) in methanol (2 mL) was added NaBH₄ (42.1 mg, 1.113 mmol). Thesolution was stirred at room temperature for 30 min. The mixture wasdiluted with water and extracted with EA. The organic phase was washedwith brine, driver over Na₂SO₄, filtrated and concentrated in vacuo togive the title compound (120 mg, 0.588 mmol, 79% yield) as brown oil.

LC-MS (ESI): m/z 205 [M+H]⁺; 1.36 min (ret time).

D202 Methyl 4-(bromomethyl)-3-fluorobenzoate

To a mixture of 1-bromopyrrolidine-2,5-dione (3.18 g, 17.84 mmol) inperchloromethane (20 mL) was added methyl 3-fluoro-4-methylbenzoate (2.5g, 14.87 mmol) and(E)-2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (0.244 g, 1.487mmol). The resulting mixture was stirred at 70° C. for 2 hours. Themixture was concentrated in vacuo and the crude was purified by columnchromatography on silica gel eluting with petroleum ether/EtOAc (100% to20/1) to give the title compound (2.44 g, 8.62 mmol, 58.0% yield) asyellow oil.

LC-MS (ESI): m/z 247 [M−H]⁺; 1.76 min (ret time).

D203 Methyl 4-((3,3-difluoropiperidin-1-yl)methyl)-3-fluorobenzoate

A mixture of methyl 4-(bromomethyl)-3-fluorobenzoate (200 mg, 0.810mmol), 3,3-difluoropiperidine (98 mg, 0.810 mmol) and potassiumcarbonate (336 mg, 2.429 mmol) in acetonitrile (20 mL) was stirred at80° C. for 2 hours. The mixture was then diluted with CH₂Cl₂ and washedwith water (30 mL×2). The organic phase was dried over Na₂SO₄, filteredand concentrated in vacuo to give the title compound (270 mg, 0.459mmol, 56.7% yield) as light yellow oil.

LC-MS (ESI): m/z 288 [M+H]⁺; 1.53 min (ret time).

D204 (4-((3,3-Difluoropiperidin-1-yl)methyl)-3-fluorophenyl)methanol

To a solution of methyl4-((3,3-difluoropiperidin-1-yl)methyl)-3-fluorobenzoate (270 mg, 0.940mmol) in THF (10 mL) was added LiAlH₄ (71.3 mg, 1.880 mmol) at 0° C. Themixture was stirred at room temperature for 1 hour. The mixture wasquenched with water (0.1 mL), 15% NaOH solution (0.1 mL) and water (0.1mL). The mixture was filtered and washed with EtOAc (20 mL). Thefiltrate was concentrated in vacuo to give the title compound (223 mg,0.826 mmol, 88% yield) as colorless oil.

LC-MS (ESI): m/z 260 [M+H]⁺; 1.20 min (ret time).

D205 4-((4,4-Difluorocyclohexyl)oxy)-3,5-difluorobenzoic Acid

To a solution of 3,4,5-trifluorobenzoic acid (1.14 g, 6.5 mmol) and4,4-difluorocyclohexanol (800 mg, 6.5 mmol) in DMF (50 mL) was added NaH(60% in mineral oil, 1.04 g, 25.9 mmol) at 0° C. The mixture was stirredat room temperature for 6 hours. The mixture was poured into ice-water(100 mL). The mixture was acidified with conc. HCl to pH<7, extractedwith EA (50 mL×3), brine, dried over Na₂SO₄, filtered and evaporated togive the title compound (1.9 g, yield 100%) as a yellow solid.

D206 (4-((4,4-Difluorocyclohexyl)oxy)-3,5-difluorophenyl)methanol

To a solution of BH₃-THF (1 M in THF, 14.4 mL, 14.4 mmol) was added4-((4,4-difluorocyclohexyl)oxy)-3,5-difluorobenzoic acid (2.1 g, 7.2mmol) in THF (20 mL) at 0° C. The mixture was heated to reflux andstirred for 3 hours. The mixture was cooled to room temperature andquenched with MeOH (10 mL). The solution was then concentrated andpurified by prep-TLC (DCM/MeOH=30/1) to give the title compound (1.4 g,yield 70%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 6.97-6.90 (m, 2H), 4.63 (s, 2H), 4.37-4.36(m, 1H), 2.34-1.36 (m, 8H).

D207 4-(Benzyloxy)-3,5-difluorobenzoic Acid

To a solution of 3,4,5-trifluorobenzoic acid (3.52 g, 20 mmol) andphenylmethanol (2.16 g, 20 mmol) in DMF (50 mL) was added NaH (60% inmineral oil, 3.2 g, 80 mmol) at 0° C. The mixture was stirred at roomtemperature overnight. The mixture was quenched with ice water (100 mL).The mixture was acidified with conc. HCl to pH<7, extracted with EA (50mL×3). The organic layer was washed with brine, dried over Na₂SO₄,filtered, evaporated and purified by flash chromatograph on silica gel(PE/EA=4/1) to give the title compound (5.0 g, yield 88%) as a yellowsolid.

¹H NMR (300 MHz, CDCl₃): δ 7.64-7.61 (m, 2H), 7.46-7.33 (m, 5H), 5.31(s, 2H).

D208 Methyl 4-(benzyloxy)-3,5-difluorobenzoate

A solution of 4-(benzyloxy)-3,5-difluorobenzoic acid (5.0 g, 18.9 mmol)and conc H₂SO₄ (1 mL) in MeOH (50 mL) was heated to reflux and stirredovernight. The solution was evaporated and treated with water (30 mL).The mixture was extracted with EA (50 mL×3). The organic layer waswashed with brine, dried over Na₂SO₄ and concentrated. The residue waspurified by flash chromatograph on silica gel (PE/EA=20/1) to give thetitle compound (4.6 g, yield 88%) as yellow oil.

¹H NMR (300 MHz, CDCl₃): δ 7.58-7.53 (m, 2H), 7.45-7.32 (m, 5H), 5.28(s, 2H), 3.89 (s, 3H).

D209 Methyl-3,5-difluoro-4-hydroxybenzoate

A mixture of methyl 4-(benzyloxy)-3,5-difluorobenzoate (4.6 g, 16.5mmol) and Pd/C (10% wet, 200 mg) in MeOH (30 mL) was stirred at roomtemperature under H₂ (1 atm) for 4 hours. The mixture was filtered andevaporated to give the title compound (2.3 g, yield 74%) as a yellowsolid.

¹H NMR (300 MHz, CDCl₃): δ 7.64-7.61 (m, 2H), 3.91 (s, 3H).

D210 Methyl 3,5-difluoro-4-(2-fluoroethoxy)benzoate

A mixture of methyl 3,5-difluoro-4-hydroxybenzoate (1.4 g, 7.45 mmol),1-bromo-2-fluoroethane (946 mg, 7.45 mmol), Cs₂CO₃ (2.9 g, 8.9 mmol) inacetonitrile (30 mL) was stirred at 70° C. for 4 hours. The reactionmixture was washed with water, extracted with EA (50 mL×2), dried overNa₂SO₄, filtrated, concentrated. The crude was purified by flashchromatography on silica gel (PE/EA=4:1) to give the title compound (1.5g, yield 87%) as colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 7.57-7.54 (m, 2H), 4.77 (t, J=3.9 Hz, 1H),4.61 (t, J=3.9 Hz, 1H), 4.51-4.48 (m, 1H), 4.41-4.39 (m, 1H), 3.88 (s,3H).

D211 (3,5-Difluoro-4-(2-fluoroethoxy)phenyl)methanol

To a mixture of methyl 3,5-difluoro-4-(2-fluoroethoxy)benzoate (1.5 g,6.4 mmol) in THF (20 mL) was added LiAlH₄ (243 mg, 6.4 mmol) at 0° C.The mixture was stirred at 0° C. for 1 hour. MeOH was added to quenchthe reaction. Potassium sodium tartrate (sat. 10 mL) was added and themixture was stirred at room temperature 1 hour. The mixture was filteredand the filtrate was evaporated and purified by flash chromatography onsilica gel (PE/EA=4/1 to 1/1) to give the title compound (1.16 g, yield89%) as colorless oil.

¹H NMR (300 MHz, CDCl₃): δ 6.96-6.87 (m, 2H), 4.80-4.77 (m, 1H),4.64-4.60 (m, 3H), 4.42-4.39 (m, 1H), 4.31-4.29 (m, 1H), 2.09 (t, J=6.0Hz, 1H).

D212 5-(Hydroxymethyl)-2-methylbenzonitrile

To an ice-cold solution of 5-formyl-2-methylbenzonitrile (0.5 g, 3.44mmol) in 1:1 MeOH/2-MeTHF (9 mL) was added NaBH₄ (0.145 g, 3.83 mmol),and the reaction mixture was stirred for 3 h. The reaction mixture wasdiluted with saturated NH₄Cl which resulted in a grayish whiteprecipitate. The aqueous layer was extracted with EtOAc (3×100 mL). Thecombined organics were washed with brine, dried on Na₂SO₄, filtered, andconcentrated under reduced pressure to provide5-(hydroxymethyl)-2-methylbenzonitrile (460 mg, 3.13 mmol, 91% yield) asa moderately viscous light-yellow liquid.

LC-MS (ESI): m/z 148[M+H]⁺; 0.56 min (ret time).

D213(S)-6-(4-bromophenethoxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

To a solution of(S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-oneand 2-(4-bromophenyl)ethanol (103 mg, 0.51 mmol) in DMF (5 mL) was addedNaH (60% in mineral oil, 38 mg, 0.94 mmol) at 0° C. The reaction mixturewas stirred at room temperature for 2 h. The reaction mixture wasconcentrated and the residue was quenched with water (40 mL), extractedwith EtOAc (40 mL×3). The combined organic layers were dried overanhydrous Na₂SO₄, filtered, concentrated under reduced pressure andpurified by prep-HPLC to give the title compound (40 mg, yield 23%) as awhite solid.

LC-MS (ESI): m/z 380[M+H]⁺; 2.26 min (ret time).

D214 (R)-3-((3-fluorophenyl)ethynyl)-8,9,9a,10tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3] oxazin-1(6H)-one

A mixture of(R)-3-chloro-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one(90 mg, 0.40 mmol), 1-ethynyl-3-fluorobenzene (96 mg, 0.80 mmol),Pd(PPh₃)₄ (23 mg, 0.02 mmol) and CuI (8 mg, 0.04 mmol) in TEA/MeCN (2mL/2 mL) was stirred overnight at room temperature under N₂. The mixturewas evaporated and purified by TLC (DCM/MeOH=20/1) to give the titlecompound (25 mg, yield 20%) as a yellow solid.

LC-MS (ESI): m/z 312[M+H]⁺; 1.89 min (ret time).

D215(S)-6-((3-fluorophenyl)ethynyl)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

A mixture of(S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(90 mg, 0.42 mmol), 1-ethynyl-3-fluorobenzene (101 mg, 0.84 mmol),Pd(PPh₃)₄ (24 mg, 0.021 mmol) and CuI (8 mg, 0.042 mmol) in TEA/MeCN (1mL/1 mL) was stirred at RT under N₂ overnight. The reaction mixture wasfiltered and concentrated, the residue was purified by prep TLC(DCM/MeOH=20:1) to give the target compound (30 mg, yield 24%) as ayellow solid.

LC-MS (ESI): m/z 298[M+H]⁺; 1.85 min (ret time).

D216(S)-6-((2,4-difluorophenyl)ethynyl)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

A mixture of(S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(100 mg, 0.47 mmol), 1-ethynyl-2,4-difluorobenzene (97 mg, 0.70 mmol),Pd(PPh₃)₄ (27 mg, 0.024 mmol) and CuI (9 mg, 0.047 mmol) in TEA/MeCN (2mL/2 mL) was stirred at RT under N₂ overnight. The reaction mixture wasconcentrated, the residue was purified by prep HPLC (Column: XB C18,4.6×33 mm; Mobile phase: A: H2O, B: MeCN, 20-95% B) to give the titlecompound (50 mg, yield 34%) as a light yellow solid.

LC-MS (ESI): m/z 316 [M+H]⁺; 1.89 min (ret time).

D217(S)-3-((3-fluorophenyl)ethynyl)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2c]-pyrimidin-1(6H)-one

A mixture of(S)-3-chloro-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one(90 mg, 0.43 mmol), 1-ethynyl-3-fluorobenzene (102 mg, 0.86 mmol),Pd(PPh₃)₂Cl₂ (15 mg, 0.02 mmol), DBU (13 mg, 0.09 mmol), P(n-Bu)₃ (8 mg,0.04 mmol) and Cs₂CO₃ (168 mg, 0.52 mmol) in DMF (2 mL) was purged withN₂. The reaction mixture was heated under microwave condition at 150° C.for 10 min. Then the reaction was evaporated under reduced pressure. Theresidue was purified by silica gel chromatography (MeOH/DCM=1/30) togive the title compound (30 mg, 24%) as a yellow solid.

LC-MS (ESI): m/z 296 [M+H]⁺; 1.98 min (ret time).

D218(R)-3-(4-bromophenethoxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

To a solution of(R)-3-chloro-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one(100 mg, 0.47 mmol) and 2-(4-bromophenyl)ethanol (105 mg, 0.52 mmol) inDMF (5 mL) was added NaH (60% in mineral oil, 38 mg, 0.94 mmol) at 0° C.The reaction mixture was stirred at room temperature for 2 h. Thereaction mixture was concentrated. The residue was dissolved with water(40 mL), extracted with EtOAc (40 mL×3). The combined organic layerswere dried over anhydrous Na₂SO₄, concentrated under reduced pressureand purified by prep-HPLC to give the title compound (75 mg, yield 42%)as a white solid.

LC-MS (ESI): m/z 376 [M+H]⁺; 2.36 min (ret time).

D219(S)-7-(4-bromophenethoxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

To a solution of(S)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one(100 mg, 0.44 mmol) and 2-(4-bromophenyl)ethanol (96 mg, 0.48 mmol) inDMF (5 mL) was added NaH (60% in mineral oil, 35 mg, 0.88 mmol) at 0° C.The reaction mixture was stirred at room temperature for 2 h. Thereaction mixture was concentrated. The residue was dissolved with water(40 mL), extracted with EA (40 mL×3). The combined organic layers weredried over anhydrous Na₂SO₄, concentrated under reduced pressure andpurified by prep-HPLC to give the title compound (90 mg, yield 52%) as awhite solid.

LC-MS (ESI): m/z 394 [M+H]⁺; 2.21 min (ret time).

D220(R)-7-((3-fluorophenyl)ethynyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

A mixture of(R)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one(80 mg, 0.35 mmol), 1-ethynyl-3-fluorobenzene (85 mg, 0.70 mmol),Pd(PPh₃)₄ (20 mg, 0.0175 mmol) and CuI (7 mg, 0.035 mmol) in TEA (2 mL)was degassed with N₂. The reaction was stirred at 120° C. for 10 minunder microwave irradiation. The mixture was evaporated and purified byTLC (DCM/MeOH=30/1) to give title compound (20 mg, yield 15%) as ayellow solid.

LC-MS (ESI): m/z 312 [M+H]⁺; 1.65 min (ret time).

D221(S)-7-((3-fluorophenyl)ethynyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c]-[1,4]oxazin-9(1H)-one

A mixture of(S)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one(100 mg, 0.44 mmol), 1-ethynyl-3-fluorobenzene (106 mg, 0.88 mmol),Pd(PPh₃)₄ (25 mg, 0.022 mmol) and CuI (8 mg, 0.044 mmol) in TEA/MeCN (2mL/2 mL) was stirred overnight at room temperature under N₂. The mixturewas evaporated and purified by TLC (DCM/MeOH=20/1) to give the titlecompound (30 mg, yield 22%) as a yellow solid. LCMS: Rt=1.926 min,[M+H]⁺=312.

LC-MS (ESI): m/z 312 [M+H]⁺; 1.93 min (ret time).

D222(S)-7-((2,4-difluorophenyl)ethynyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

A mixture of(S)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one(100 mg, 0.44 mmol), 1-ethynyl-2,4-difluorobenzene (91 mg, 0.66 mmol),Pd(PPh₃)₄ (25 mg, 0.022 mmol) and CuI (8 mg, 0.044 mmol) in TEA/MeCN (2mL/2 mL) was stirred at RT under N₂ overnight. The reaction mixture wasconcentrated, the residue was purified by prep TLC (DCM/MeOH=30:1) togive the title compound (50 mg, yield 33%) as a light yellow solid.

LC-MS (ESI): m/z 329 [M+H]⁺; 1.93 min (ret time).

D223 2-Cyclobutoxy-5-formylbenzonitrile

A suspension of 2-fluoro-5-formylbenzonitrile (300 mg, 2.012 mmol) andcesium carbonate (730 mg, 2.241 mmol) in acetonitrile (2 mL) was stirredat ambient temperature for 18 hrs, and then heated at 60° C. for 30 min.The reaction mixture was poured into water (2 mL) and extracted withEtOAc (3×1 mL). The combined organic layer was washed with brine, dried(anhydrous Na₂SO₄), filtered, and concentrated. The crude was purifiedon a Combiflash silica cartridge (12 g) (0-80% EtOAc/hexanes) then byreverse phase prep HPLC [10-90% CH₃CN/H₂O (0.1% NH₄OH)] to give thetitle compound (60 mg, 0.298 mmol, 14.82% yield) as a white solid.

LC/MS: m/z 202.4 (M+H)⁺, 0.85 min (ret. time)

D224 2-(Cyclopentyloxy)-5-formylbenzonitrile

A suspension of 2-fluoro-5-formylbenzonitrile (300 mg, 2.012 mmol) andpotassium carbonate (700 mg, 5.06 mmol) in DMSO (2 mL) was sealed andheated in Biotage Initiator using initial high to 120° C. for 1 h. Thereaction mixture was poured into water (6 mL) and extracted with EtOAc(5×2 mL). The combined organic layer was washed with brine, dried(anhydrous Na₂SO₄), filtered, and concentrated. The crude was purifiedon a Combiflash silica cartridge (12 g) (0-80% EtOAc/hexanes) thenfurther purified by prep reverse phase HPLC [10-90% CH₃CN/H₂O (0.1%NH₄OH)] to give the title compound (23 mg, 0.107 mmol, 5.31% yield) as ahazy gummy solid.

LC/MS: m/z 216.6 (M+H)⁺, 0.94 min (ret. time)

D225 tert-Butyl7-((2,3-difluorophenyl)ethynyl)-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2(9H)-carboxylate

A solution of bis(triphenylphosphine)palladium(II) chloride (4 mg, 5.70μmol), triphenylphosphine (3 mg, 0.011 mmol), copper(I) iodide (3 mg,0.016 mmol), TEA (0.68 mL, 4.88 mmol), 1-ethynyl-2,3-difluorobenzene(0.11 mL, 0.796 mmol) and tert-butyl7-chloro-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2(9H)-carboxylate(0.204 g, 0.624 mmol) in THF (2.5 mL) was heated at 65° C. overnight.After cooling to room temperature, the reaction was concentrated. Thecrude was purified on a Combiflash silica cartridge (12 g) (0-20%MeOH/DCM) to give the title compound (171 mg, 0.399 mmol, 63.9% yield)as an amorphous white solid.

LC/MS: m/z 429.2 (M+H)⁺, 0.79 min (ret. time)

D2267-((2,3-Difluorophenyl)ethynyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one

A mixture of7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one(400 mg, 1.64 mmol, 1.0 equiv), 1-ethynyl-2,3-difluorobenzene (272 mg,1.97 mmol, 1.2 equiv), and Et₃N (1.2 mL, 5.0 equiv) in 8 mL of THF wasbubbled with N₂ at rt for 10 min, followed by addition of PdCl₂ (PPh₃)₂(115 mg, 0.1 equiv) and CuI (31 mg, 0.1 equiv). The resulting mixturewas capped and heated at 90° C. for 12 hrs. The cooled mixture wasfiltered through celite and the filtrate was concentrated. The residuewas dissolved in 10% MeOH in DCM (20 mL) and washed with water (3 mL),diluted with saturated NaHCO₃ (2 mL). The aqueous was back extractedwith 10% MeOH in DCM (2×5 mL). The combined organic was dried overNa₂SO₄, filtered, and concentrated. The crude material was purified byTeledyne-Isco Combiflash (40 g silica gel cartridge) to give the titlecompound (293 mg) as a light tan-colored solid.

LC/MS: m/z 346 (M+H)⁺, 0.634 min (ret. time).

¹H NMR (400 MHz, 1:1 CD₂Cl₂: CD₃OD): δ 7.29 (t, J=6.27 Hz, 1H),7.26-7.17 (m, 1H), 7.13-7.02 (m, 1H), 5.92 (s, 1H), 4.31-4.22 (m, 1H),4.22-4.11 (m, 1H), 4.00-3.92 (m, 1H), 3.74-3.67 (m, 1H), 3.40-3.29 (m,1H), 2.84-2.73 (m, 2H), 2.54-2.50 (m, 1H).

D227 tert-Butyl7-((3,4-difluorobenzyl)oxy)-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2(9H)-carboxylate

To a solution of tert-butyl7-chloro-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2(9H)-carboxylate (2.832 g, 8.67 mmol) and(3,4-difluorophenyl)methanol (1.249 g, 8.67 mmol) in anhydrous 2-Me-THF(65 mL) was added NaH (0.867 g, 21.67 mmol) and the reaction was stirredat room temperature. Saturated NH₄Cl (50 mL) was added and the aqueouslayer was extracted with EtOAc (2×25 mL). The combined organic layer wasconcentrated and purified by flash chromatography to give 3.303 g (88%)of the title compound as a sticky pale brown solid.

LC/MS: m/z 435.0 (M+H)⁺, 0.86 min (ret. time)

¹H NMR (400 MHz, CD₂Cl₂): δ 7.31-7.22 (m, 1H), 7.20-7.06 (m, 2H), 5.31(br. s., 2H), 5.02 (s, 1H), 4.13 (dd, J=8.9, 11.7 Hz, 3H), 3.94-3.79 (m,1H), 3.66 (s, 1H), 3.48-3.37 (m, 1H), 3.21-3.08 (m, 1H), 2.95-2.63 (m,2H), 1.46 (s, 9H)

D2287-((3,4-Difluorobenzyl)oxy)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

A mixture of tert-butyl7-((3,4-difluorobenzyl)oxy)-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2(9H)-carboxylate (3 g, 6.91 mmol) in TFA (20mL, 260 mmol) was stirred at room temperature for 30 min. The mixturewas then concentrated. This solid was taken up in MeOH (30 mL), and BIORAD AG 4-X4 resin (16 g) was added. The mixture was filtered, and thefiltercake was rinsed with MeOH (2×30 mL). The filtrate was concentratedunder reduced pressure and dried under high vacuum to give 1.604 g (70%)of the title compound as a sticky brown solid.

LC/MS: m/z 335.0 (M+H)⁺, 0.47 min (ret. time)

¹H NMR (400 MHz, METHANOL-d₄): δ 7.40-7.31 (m, 1H), 7.29-7.17 (m, 2H),5.34-5.20 (m, 2H), 4.21-4.06 (m, 1H), 4.02-3.83 (m, 1H), 3.70-3.50 (m,2H), 3.17 (d, J=12.8 Hz, 2H), 3.05-2.89 (m, 1H), 2.79-2.59 (m, 2H).

D229 tert-Butyl(1-(7-((3,4-difluorobenzyl)oxy)-9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2-carbonyl)cyclopropyl)carbamate

A solution of 50 wt % T3P in EtOAc (0.11 mL, 0.185 mmol) was addeddropwise over 1 min, 45 sec to a solution of7-((3,4-difluorobenzyl)oxy)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one (50 mg, 0.150 mmol), 1-((tertbutoxycarbonyl)amino)-cyclopropanecarboxylic acid (31 mg, 0.154 mmol), and anhydrousTEA (0.09 mL, 0.649 mmol) in anhydrous DCM (1 mL) in a 2 dram vial. Thevial was capped, and the reaction was stirred at room temperature. After25 min at room temperature, the reaction was washed with 10% citric acid(1 mL) and saturated NaHCO₃ (1 mL). The mixture was concentrated and thecrude product was then purified by flash chromatography to give 35.9 mg(46%) of the title compound.

LC/MS: m/z 518.1 (M+H)⁺ 0.82 min (ret. time)

The following intermediates D230-D237 listed in Table 1 were prepared bya procedure similar to that described for D229:

TABLE 1

NO # R Yield LC/MS Name D230

47% m/z 534.1 (M + H)⁺ 0.91 min (ret. time) tert-butyl(4-(7-((3,4-difluorobenzyl)- benzyl)oxy)-9-oxo-3,4,11,11a-tetra- hydro1H-pyrazino[1′,2′:3,4]imidazo- [1,2-c]pyrimidin-2(9H)-yl)-2-methyl-4-oxobutan-2-yl)-carbamate D231

22% m/z 520.1 (M + H)⁺ 0.83 min (ret. time)tert-butyl(1-(7-((3,4-difluorobenzyl)- oxy)-9-oxo-3,4,11,11a-tetrahydro-1Hpyrazino[1′,2′:3,4]imidazo[1,2-c]- pyrimidin-2(9H)-yl)-2-methyl-1-oxopropan-2-yl)carbamate D232

55% m/z 518.1 (M + H)⁺ 0.81 min (ret. time) (2S)-tert-butyl2-(7-((3,4-difluoro- benzyl)oxy)-9-oxo 2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]- imidazo[1,2-c]pyrimidine-2-carbonyl)azetidine-1-carboxylate D233

46% m/z 532.2 (M + H)⁺ 083 min (ret. time) (2S)-tert-butyl2-(7-((3,4-difluoro- benzyl)oxy)-9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]- imidazo[1,2-c]pyrimidine-2-carbonyl)pyrrolidine-1-carboxylate D234

35% m/z 550.2 (M + H)⁺ 0.81 min (ret. time) (2S,4S)-tert-butyl2-(7-((3,4-difluoro- benzyl)oxy)-9-oxo-2,3,4,9,11,11a-hexahydro-1Hpyrazino[1′,2′:3,4]- imidazo[1,2-c]pyrimidine-2-carbonyl)-4-fluoropyrrolidine-1- carboxylate D235

49% m/z 568.2 (M + H)⁺ 0.89 min (ret. time) (2S)-tert-butyl2-(7-((3,4-difluoro- benzyl)oxy)-9-oxo-2,3,4,9,11,11a-hexahydro-1Hpyrazino[1′,2′:3,4]- imidazo[1,2-c]pyrimidine-2-carbonyl)-4,4-difluoropyrrolidine- 1-carboxylate D236

45% m/z 532.1 (M + H)⁺ 0.85 min (ret. time) (2R)-tert-butyl2-(7-((3,4-difluoro- benzyl)oxy)-9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]- imidazo[1,2-c]pyrimidine-2-carbonyl)pyrrolidine-1-carboxylate D237

41% m/z 532.1 (M + H)⁺ 0.83 min (ret. time) tert-butyl(1-(7-((3,4-difluoro- benzyl)oxy)-9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]- imidazo[1,2-c]pyrimidine-2-carbonyl)cyclobutyl)carbamate

D238 tert-Butyl(4-(7-((3,4-difluorobenzyl)oxy)-9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2-carbonyl)tetrahydro-2H-pyran-4-yl)carbamate

A solution of HATU (57 mg, 0.150 mmol),4-((tertbutoxycarbonyl)amino)tetrahydro-2H-pyran-4 carboxylic acid (37mg, 0.151 mmol) and anhydrous TEA (0.05 mL, 0.361 mmol) in anhydrous DMF(1 mL) was stirred at room temperature for 30 min.7-((3,4-difluorobenzyl)oxy)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one(50 mg, 0.150 mmol) was then added, and stirring was continued at roomtemperature. After 1.5 h, DCM (2 mL) was added, and the mixture waswashed with 10% citric acid (1×1 mL) and saturated NaHCO₃ (1×1 mL). Themixture was concentrated and purified by flash chromatography to give30.2 mg (36%) of the title compound as a clear, colorless film.

LC/MS: m/z 562.1 (M+H)⁺, 0.82 min (ret. time)

D239 tert-Butyl(1-(7-((3,4-difluorobenzyl)oxy)-9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2-carbonyl)cyclohexyl)carbamate

The title compound D239 was prepared by a procedure similar to thatdescribed for D238 starting from1-((tertbutoxycarbonyl)amino)cyclohexanecarboxylic acid.

LC/MS: m/z 560.2 (M+H)⁺, 0.92 min (ret. time)

D240 3-(Benzylamino)oxetane-3-carbonitrile

A solution of oxetan-3-one (14.0 g, 194 mmol, 1 equiv) in 50 mL of EtOHwas added gradually to a stirred and chilled (ice bath) solution ofN-benzylamine (22.9 g, 214 mmol, 1.1 equiv) in 50 mL of EtOH in a 500 mLflask, followed by gradual addition of TMSCN (23.1 g, 233 mmol, 1.2equiv) in 50 mL of EtOH, and the final addition of NH₄Cl (3.1 g, 58mmol, 0.3 equiv) in one portion. The resulting mixture was heated in anoil bath at 80° C. for 18 h. The mixture was cooled to room temperatureand filtered. The filtrate was concentrated. The residue was partitionedbetween EtOAc (50 and 25 mL) and saturated aqueous NaHCO₃ (40 mL). Theorganic was dried over Na₂SO₄, filtered, and concentrated to give a abrownish residue (41.2 g). This material was re-dissolved in DCM,absorbed onto isolute, and divided into 3 equal portions. Purification(each portion) was performed on a Teledyne-Isco Combiflash Rfpurification system using a Redi-Sep 120 g silica gel cartridge withgradient elution of 0% EtOAc in hexane to 100% EtOAc over a 40 minperiod (the first 5 min was holding time for 0% EtOAc in hexane, flowrate at 85 mL/min, UV at 254 nm). The desired product began eluting at17 min. Appropriate fractions were combined and concentrated to give thetitle compound (32.1 g) as a clear light yellow-colored thick oil whichsolidified upon ageing.

LC/MS: m/z 188.9 (M+H)⁺, 0.70 min (ret. time). ¹H NMR (400 MHz, CDCl₃) δppm 1.98 (br. s., 1H) 3.88 (d, J=6.53 Hz, 2H) 4.48 (d, J=6.53 Hz, 2H)4.86 (d, J=6.78 Hz, 2H) 7.29-7.46 (m, 5H).

D241 3-(Benzylamino)oxetane-3-carboxylic Acid

A mixture of 3-(benzylamino)oxetane-3-carbonitrile (34.5 g, 183 mmol, 1equiv) and 61 mL of 6N NaOH (366 mmol, 2 equiv) in a 500 mL RB flask washeated in an oil bath at 110° C. for 20 min. The mixture was cooled tort, and then chilled in an ice bath. To the cold mixture was added 6 NHCl to adjust pH to 7. A thick suspension resulted, and was let settledat room temperature for 30 min, followed by filtration. The cake waswashed with water (40 mL) and aspirated under vacuum at room temperaturefor 2 days. The solids were further dried under high vacuum over P₂O₅ atroom temperature for 8 h to give the title compound (27.1 g) as lightbeige powdery solids.

LC/MS: m/z 207.9 (M+H)⁺, 0.09-0.28 min (ret. time). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 3.72 (s, 2H) 4.45 (d, J=6.27 Hz, 2H) 4.69 (d, J=6.02 Hz,2H) 7.22-7.30 (m, 1H) 7.30-7.43 (m, 4H).

D242 (3-(Benzylamino)oxetan-3-yl)methanol

3-(Benzylamino)oxetane-3-carboxylic acid (8.0 g, 38.6 mmol, 1 equiv) wasadded as solids portionwise (in small portions) to a stirred chilled(ice bath) solution of LAH (2M in THF, 50 mL, 100 mmol, 2.6 equiv) in150 mL of THF in a 1 L flask fitted with a large magnetic stirring bar,a thermometer, and under N₂. The addition temperature (internal) wasaround 4-6° C. Addition took 1 h to complete. The mixture was stirred inthe ice bath for another 30 min. The mixture was diluted with another125 mL of THF, followed by careful addition of 16.7 mL of saturatedNa₂SO₄ solution. The internal temperature stayed around 15° C. and neverexceeded 20° C. After completion of Na₂SO₄ solution addition, the icebath was removed. The resulting whitish mixture was stirred at roomtemperature for 20 min. The whitish suspension was filtered throughcelite. The cake was washed repeatedly with EtOAc (total 400 mL). Thefiltrate was dried over Na₂SO₄, filtered, and concentrated. The residuewas re-dissolved in DCM, and absorbed onto Isolute. Purification wasperformed on a Teledyne-Isco Combiflash Rf purification system using aRedi-Sep 120 g silica gel cartridge with gradient elution of 0% A in DCMto 50% A in DCM over a 40 min period (the first 2 min was holding timefor 0% A in DCM, A was a mixture of 80/800/3200 NH₄OH/MeOH/DCM, flowrate at 85 mL/min, UV at 254 nm). The desired product eluted at 17-22min. Appropriate fractions were combined and concentrated to provide thetitle compound (5.41 g) as a brownish thick oil, which solidified uponageing.

LC/MS: m/z 193.9 (M+H)⁺, 0.09-0.36 min (ret. time). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 3.62 (d, J=5.52 Hz, 2H) 3.77 (br. s., 2H) 4.27 (d, J=6.02Hz, 2H) 4.45 (d, J=6.02 Hz, 2H) 4.86 (t, J=5.65 Hz, 1H) 7.17-7.26 (m,1H) 7.30 (t, J=7.40 Hz, 2H) 7.34-7.43 (m, 2H).

D243 (3-Aminooxetan-3-yl)methanol

A mixture of (3-(benzylamino)oxetan-3-yl)methanol (6.50 g, 33.6 mmol)and Pd(OH)₂ (20% on carbon, 618 mg) in 65 mL of MeOH in a 500 mL Parrbottle was hydrogenated under 50-55 psi at room temperature for a totalof 12 h. Additional Pd(OH)₂ (200 mg) were added as a slurry in 4 mL ofMeOH. Hydrogenation at 50-55 psi was continued for another 4 h. Themixture was filtered through celite and rinsed with MeOH (15 mL). Thefiltrate was concentrated to provide the title compound (3.73 g) as alight greenish thick oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.83 (s, 2H) 4.45 (d, J=6.53 Hz,2H) 4.51 (d, J=6.78 Hz, 2H).

D244 (3-((2,6-Dichloropyrimidin-4-yl)amino)oxetan-3-yl)methanol

(3-Aminooxetan-3-yl)methanol (3.46 g, 33.6 mmol, 1 equiv) was stirredwith DIPEA (5.6 mL, 32.1 mmol, 3 equiv) in 12 mL of THF cooled in awater bath (no ice). To this stirred mixture was added2,4,6-trichloropyrimidine (1.35 mL, 11.8 mmol, 1.1 equiv) over a 3 minperiod. The mixture was stirred at room temperature for 48 h. Themixture was concentrated. The residue was partitioned between water (15mL), and saturated NaHCO₃ (10 mL) and EtOAc (100, 50 and 30 mL). Theorganic was dried over Na₂SO₄, and filtered. The filtrate was directlyabsorbed onto Isolute and concentrated. The resulting adsorbed Isolutematerial was splitted into two equal halves. Purification (each portion)was performed on a Teledyne-Isco Combiflash Rf purification system usinga Redi-Sep 120 g silica gel cartridge with gradient elution of 0% A inhexane to 100% A in hexane over a 35 min period (A was a mixture of 2.5%MeOH in EtOAc, flow rate at 85 mL/min, UV at 254 nm). Three large peakseluted out. The last peak was the desired product (eluting at 25 min).Appropriate fractions were combined and concentrated to provide thetitle compound (4.03 g) as a white solid residue.

LC/MS: m/z 249.8 (M+H)⁺, 0.61 min (ret. time). ¹H NMR (400 MHz, DMSO-d₆)δ ppm 3.79 (d, J=5.52 Hz, 2H) 4.41-4.61 (m, 4H) 5.19 (t, J=5.52 Hz, 1H)6.54 (s, 1H) 8.77 (br. s., 1H).

D245 7-Chloro-1H-spiro[imidazo[1,2-c]pyrimidine-2,3′-oxetan]-5(3H)-one

A suspension of(3-((2,6-dichloropyrimidin-4-yl)amino)oxetan-3-yl)methanol (1.67 g, 6.7mmol, 1 equiv) and DIPEA (5.8 mL, 33.4 mmol, 5 equiv) in 20 mL of THF ina 200 mL flask was sonicated at room temperature until most solidparticles dissolved and turned into a cloudy mixture. This mixture waschilled in an ice bath, and followed with addition of methanesulfonicanhydride (2.91 g, 16.69 mmol, 2.5 equiv) portionwise as solids. Themixture was stirred naturally (ice not renewed). After 1 h, the reactionwas complete. The mixture was concentrated. The brownish oily residuewas taken up in 2.9 mL of DIEPA (2.5 equiv), 4 mL of propionitrile and10 mL of water. The resulting mixture was heated at 100° C. for 90 min,cooled to room temperature, and aged overnight. The resulting suspensionwas stored in the refrigerator (4° C.) for 3 h, followed by filtration.The solids collected were washed with water (4 mL) and TBME (3 mL), anddried under high vacuum to provide the title compound (621 mg) as beigesolid.

LC/MS: m/z 213.9 (M+H)⁺, 0.11-0.26 min (ret. time), eluting at thesolvent front.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 4.31 (s, 2H) 4.69 (q, J=7.28 Hz, 4H)5.68 (s, 1H) 9.72 (s, 1H).

D246 tert-Butyl7-chloro-5-oxo-3,5-dihydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,3′-oxetane]-1-carboxylate

A mixture of7-chloro-1H-spiro[imidazo[1,2-c]pyrimidine-2,3′-oxetan]-5(3H)-one (207mg, 1.1 mmol, 1 equiv), Boc-anhydride (278 mg, 1.3 mmol, 1.2 equiv),DMAP (6.5 mg, 0.05 mmol, 0.05 equiv) and DIPEA (464 uL, 2.7 mmol, 2.5equiv) in 5 mL of THF in a 20 mL vial was stirred at room temperaturefor 4 h. The suspension was filtered. The cake was washed with TBME (3mL) and dried under vacuum to give the title compound (258 mg) as anoff-white powdery solid.

LC/MS: m/z 314.0 (M+H)⁺, 0.72 min (ret. time).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.60 (s, 9H) 4.44 (s, 2H) 4.63 (d,J=7.28 Hz, 2H) 5.15 (d, J=7.53 Hz, 2H) 6.61 (s, 1H).

D2477-Chloro-1-methyl-1H-spiro[imidazo[1,2-c]pyrimidine-2,3′-oxetan]-5(3H)-one

To a mixture of7-chloro-1H-spiro[imidazo[1,2-c]pyrimidine-2,3′-oxetan]-5(3H)-one (533mg, 2.5 mmol, 1 equiv) and Cs₂CO₃ (1.63 g, 5.0 mmol, 2 equiv) in 20 mLof propionitrile in a 40 mL vial was added dimethyl sulfate (191 uL, 2.0mmol, 0.8 equiv). The mixture was heated at 90° C. for 40 min. The hotmixture was filtered through celite. The cake was washed with hot ACN(4×10 mL) and 10% ACN in DCM (20 mL). The filtrate was concentrated togive a brownish solid residue (518 mg), which was redissolved in 10% ACNin DCM and adsorbed onto Isolute. Purification was performed on aTeledyne-Isco Combiflash Rf purification system using a Redi-Sep 80 gsilica gel cartridge with gradient elution of 0% A in DCM to 100% A inDCM over a 35 min period (A was a mixture of 80/800/3200 NH₄OH/MeOH/DCM,flow rate at 60 mL/min, UV at 254 nm). The desired product eluted at16.5 min. Appropriate fractions were combined and concentrated to givethe title compound (193 mg) as a beige powdery solid.

LC/MS: m/z 227.9 (M+H)⁺, 0.36 min (ret. time).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.17 (s, 3H) 4.32 (s, 2H) 4.66 (d,J=8.03 Hz, 2H) 4.91 (d, J=8.03 Hz, 2H) 5.96 (s, 1H).

D248 (4-Aminotetrahydro-2H-pyran-4-yl)methanol

To a 100 mL round bottomed flask,4-aminotetrahydro-2H-pyran-4-carboxylic acid (5 g, 34.4 mmol) was addedto methanol (50 mL) and solution was cooled in ice. To this was addedthionyl chloride (5.03 mL, 68.9 mmol) dropwise and solution was stirredat 0° C. for 1 h then heated to 50° C. and stirred overnight. Solventwas evaporated to a white solid, which was taken up in sat. Na₂CO₃,extracted with DCM, washed with brine, and dried (MgSO4) and evaporatedto yield methyl 4-aminotetrahydro-2H-pyran-4-carboxylate (2.86 g, 17.9mmol, 52.1% yield) as a pale yellow liquid.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.15-1.27 (m, 2H) 1.43 (s, 2H) 1.82 (ddd,J=13.36, 9.22, 4.02 Hz, 2H) 3.32-3.41 (m, 2H) 3.48 (s, 3H) 3.54-3.64 (m,2H).

To a 200 mL round bottom flask in an ice bath was added lithium aluminumhydride (1.34 g, 35.2 mmol) with steady stirring at 0° C. A solution ofmethyl 4-aminotetrahydro-2H-pyran-4-carboxylate (2.8 g, 17.59 mmol) intetrahydrofuran (THF) (10 ml) was added dropwise via addition funnel.Upon addition of the substrate, the reaction was allowed to stir, andwarmed naturally to room temperature for 2 h. The reaction was thenquenched by dropwise addition of 5.9 mL of saturated Na₂SO₄ (quenchingformula: 4.4 mL/g of LAH). White precipitate formed was filtered and thesolution was evaporated to yield(4-aminotetrahydro-2H-pyran-4-yl)methanol (1.35 g, 10.29 mmol, 58.5%yield) as an oil.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.43 (d, J=13.80 Hz, 2H) 1.69 (ddd,J=13.30, 9.16, 4.14 Hz, 2H) 3.42 (s, 2H) 3.65-3.86 (m, 4H); LCMS:(MH+)=132 rt=0.08 min.

D249(4-((2,6-Dichloropyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-yl)methanol

To a 100 ml round bottomed flask was added(4-aminotetrahydro-2H-pyran-4-yl)methanol (0.68 g, 5.18 mmol in 10 mL ofTHF at 0° C. To this was added sodium hydride (0.622 g, 15.55 mmol) andsolution was stirred for 30 min. 2,4,6-trichloropyrimidine (0.594 mL,5.18 mmol) dissolved in tetrahydrofuran (THF) (15 mL) was added dropwiseand then reaction was allowed to warm to RT and stirred for 4 h. Thesolution was diluted with ethyl acetate and water and the layers wereseparated, and the aqueous layer was extracted with EtOAc (3×10 mL). Thecombined organic layers were washed with saturated NaCl (1×10 mL), dried(MgSO₄), and concentrated under reduced pressure. The crude material waspurified on a Teledyne-Isco Combiflash Rf purification system. Theresidue was dissolved in 5 mL of DCM and injected on a Teledyne-IscoRediSep Rf silica gel column (12 g) and was eluted with a gradient ofDCM to 10% meoh/DCM over 10 minutes. The appropriate fractions werecollected and evaporated to yield a mixture of the two products. Thefractions were dried down and re-purified on 4 g combiflash columneluting with a gradient of 50% hexanes/ethyl acetate to 100% EtOAcyielding(4-((2,6-dichloropyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-yl)methanol(330 mg, 1.186 mmol, 22.89% yield) as a solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.41 (d, J=13.30 Hz, 2H) 1.66-1.81 (m, 2H)3.72-3.84 (m, 4H) 4.16-4.24 (m, 2H) 6.73 (s, 1H); LCMS: (MH+)=279rt=0.49 min.

D2507-Chloro-2′,3′,5′,6′-tetrahydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-pyran]-5(3H)-one

To a 25 ml round bottomed flask was added(4-((2,6-dichloropyrimidin-4-yl)amino)tetrahydro-2H-pyran-4-yl)methanol(200 mg, 0.719 mmol) and DIEA (0.377 mL, 2.157 mmol in THF (3 mL).Solution was cooled to 0° C. and stirred for 30 min. methanesulfonylchloride (0.067 mL, 0.863 mmol was added and then reaction was allowedto warm to RT and stirred 1 h. LCMS shows mesylate is formed andsolution was heated to 70° C. overnight. A white precipitate formed andwas filtered to yield7-chloro-2′,3′,5′,6′-tetrahydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-pyran]-5(3H)-one(107 mg, 0.443 mmol, 61.6% yield as a white powder.

¹H NMR (400 MHz, DMSO-d6) δ ppm 1.69-1.92 (m, 4H) 3.46-3.65 (m, 2H)3.70-3.83 (m, 2H) 3.95 (s, 2H) 6.13 (s, 1H).

D2517-Chloro-5-oxo-2′,3,3′,5,5′,6′-hexahydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-pyran]-1-carboxylate

To a 100 mL round bottomed flask was added7-chloro-2′,3′,5′,6′-tetrahydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-pyran]-5(3H)-one(900 mg, 3.73 mmol) and DMF (20 mL). To this was added 60% NaH (746 mg,18.65 mmol) and solution was stirred for 1 h. Boc₂O (0.94 mL, 5.6 mmol)was added and solution was stirred for 1 h. After 2 h, the reaction hasapparently stalled, and more 60% NaH (750 mg) was added followed byBoc₂O (0.94 mL, 5.6 mmol) and reaction stirred an additional hour at RT.Solution was treated with dropwise addition of water, until quenched,then 20 mL added followed by DCM; organics separated and aqueous washedwith DCM (2×), organics combined, washed with water (2×), brine, driedover magnesium sulfate and evaporated to a white solid. The solid wastriturated with hexanes and filtered to yield7-chloro-5-oxo-2′,3,3′,5,5′,6′-hexahydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-pyran]-1-carboxylate(687 mg, 54%).

¹H NMR (400 MHz, CDCl₃) δ ppm 0.80-0.96 (m, 2H) 1.60-1.72 (m, 11H)2.79-2.93 (m, 2H) 3.45 (t, J=12.30 Hz, 2H) 4.06-4.18 (m, 4H) 6.77 (s,1H); LCMS: (MH+)=342 rt=0.83 min.

D252(4-((2,6-Dichloropyrimidin-4-yl)(methyl)amino)tetrahydro-2H-pyran-4-yl)methanol

To a 20 ml round microwave vial was added(4-(methylamino)tetrahydro-2H-pyran-4-yl)methanol (900 mg, 6.20 mmol intetrahydrofuran (15 mL) at rt. To this was added DIEA (3.25 mL, 18.60mmol) and 2,4,6-trichloropyrimidine (0.711 mL, 6.20 mmol) and solutionwas stirred for 10 min. The reaction vessel was sealed and irradiated ina Biotage Initiator microwave using normal power setting to 100° C. for2 hours. Solution was evaporated and the residue was dissolved in DMSO(1 mL), filtered through a 0.45 m acrodisc, and purified on a GilsonHPLC (Sunfire 5 m C18 OBD 30×100 mm preparatory column), eluting at 30mL/min with a linear gradient running from 10% CH₃CN/H₂O (0.1% TFA) to90% CH₃CN/H₂O (0.1% TFA) over 10 min. The desired fractions wereconcentrated by rotovap to yield(4-((2,6-dichloropyrimidin-4-yl)(methyl)amino)tetrahydro-2H-pyran-4-yl)methanol(233 mg, 0.798 mmol, 12.87% yield).

¹H NMR (400 MHz, CDCl₃) δ ppm 2.15-2.26 (m, 4H) 3.08 (s, 3H) 3.68-3.87(m, 4H) 4.06 (s, 2H) 6.53 (s, 1H); LCMS: (MH+)=293 rt=0.71 min.

D2537-Chloro-1-methyl-2′,3′,5′,6′-tetrahydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-pyran]-5(3H)-one

To a 20 ml scintillation vial was added(4-((2,6-dichloropyrimidin-4-yl)(methyl)amino)tetrahydro-2H-pyran-4-yl)methanol(245 mg, 0.839 mmol) and DIEA (0.879 mL, 5.03 mmol) in THF (4 mL).Solution was cooled to 0° C. and stirred for 30 min. Mesyl chloride(0.196 mL, 2.52 mmol was added (turned tan cloudy) and then reaction wasallowed to warm to RT and stirred 1 h, the reaction mixture was yellowcloudy. After the reaction was complete, the solution was transferred toa 5 mL microwave vial and the reaction vessel was sealed and irradiatedin a Biotage Initiator microwave using normal power setting to 100° C.for 1 hour. Solution was evaporated over a stream of nitrogen. Themixture was filtered and rinsed with ether to yield an off whiteprecipitate which was expected product7-chloro-1-methyl-2′,3′,5′,6′-tetrahydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-pyran]-5(3H)-one(152 mg, 0.594 mmol, 70.9% yield.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.61 (d, J=12.55 Hz, 2H) 1.89-2.03 (m,2H) 2.87 (s, 3H) 3.41 (t, J=11.92 Hz, 2H) 3.89 (d, J=7.28 Hz, 2H) 4.00(s, 2H) 5.91 (s, 1H); LCMS: (MH+)=256 RT=0.42 min.

D254 tert-Butyl 4-amino-4-(hydroxymethyl)piperidine-1-carboxylate

To a 500 mL round bottom flask in an ice bath was added LAH (3.11 g, 82mmol) to THF (200 ml) with steady stirring at 0° C. The solution wasstirred 30 min and then4-amino-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (10 g, 40.9mmol) was added portionwise to the LAH suspension over the course of 20minutes and the reaction was allowed to stir, warming naturally to roomtemperature 4 h. An additional 50 mL of THF was added to facilitatestirring. The reaction was then quenched by dropwise addition of 13.7 mLof saturated Na₂SO₄ (recipe=4.4 mL solution/g LAH). The resulting whiteprecipitate was filtered and solution evaporated to yield tert-butyl4-amino-4-(hydroxymethyl)piperidine-1-carboxylate (6.32 g, 27.4 mmol,67.0% yield) as a colorless oil.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.35-1.45 (m, 2H) 1.47 (s, 9H) 1.54 (dd,J=9.91, 4.14 Hz, 2H) 3.22-3.33 (m, 2H) 3.37 (s, 2H) 3.59-3.73 (m, 2H):LCMS: (MH+)=231 rt=0.52 min.

D255 Butyl4-((2,6-dichloropyrimidin-4-yl)amino)-4-(hydroxymethyl)piperidine-1-carboxylate

To a 200 ml round bottomed flask was added tert-butyl4-amino-4-(hydroxymethyl)piperidine-1-carboxylate (6.32 g, 27.4 mmol) intetrahydrofuran (THF) (25.00 mL) at 0° C. To this was added 60% sodiumhydride (3.29 g, 82 mmol) and solution was stirred for 30 min at 0° C.2,4,6-trichloropyrimidine (3.15 mL, 27.4 mmol) dissolved intetrahydrofuran (THF) (75 mL) was added to a 500 mL flask and cooled to0° C. The alkoxide solution was added dropwise via pipette to thepyrimidine solution and the reaction was stirred at 0° C. for 1 h thenallowed to warm to RT and stirred 1 h. Water was slowly added (approx 20mL) and the solution was diluted with ethyl acetate and water and thelayers were separated, and the aqueous layer was extracted with EtOAc(3×10 mL). The combined organic layers were washed with saturated NaCl(1×10 mL), dried by using MgSO₄, and concentrated under reducedpressure. The crude material was purified on a Teledyne-Isco CombiflashRf purification system. The residue was dissolved in 5 mL of DCM andinjected on a Teledyne-Isco RediSep Rf silica gel column (80 g) and waseluted with a gradient of ethyl acetate and hexanes (50-100%) over 30minutes. The desired fractions were concentrated by rotovap givingtert-butyl4-((2,6-dichloropyrimidin-4-yl)amino)-4-(hydroxymethyl)piperidine-1-carboxylate(3.15 g, 6.10 mmol, 22.21% yield) as a yellow oil. NMR data indicates aratio of 73:27 of desired to not desired isomers. Mixture separated insubsequent step.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.22-1.41 (m, 11H) 1.47-1.64 (m, 2H)3.09-3.26 (m, 2H) 3.66 (br. s., 2H) 4.06-4.16 (m, 2H) 6.67 (s, 1H) 6.98(s, 1H); LCMS: (MH+)=378 rt=0.75 min.

D256 tert-Butyl7-chloro-5-oxo-3,5-dihydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidine]-1′-carboxylate

To a 100 ml round bottomed flask was added tert-butyl4-((2,6-dichloropyrimidin-4-yl)amino)-4-(hydroxymethyl)piperidine-1-carboxylate(3.15 g, 8.35 mmol) and DIEA (8.75 mL, 50.1 mmol) in THF (40 mL).Solution was cooled to 0° C. and stirred for 30 min. Mesyl chloride(1.952 mL, 25.05 mmol) was added (turned cloudy) and then reaction wasallowed to stir in ice for 1 h. The solution was evaporated and theresidue was taken up in DCM (5 mL) and purified on combiflash. The crudematerial was injected on a Teledyne-Isco RediSep Rf silica gel column(40 g) and was eluted with a gradient of ethyl acetate and hexanes(0-100%) over 25 minutes. The appropriate fractions were collected andevaporated to yield 3.4 g of a mixture of the two isomers by nmr.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.39-1.47 (m, 9H) 1.55-1.70 (m, 2H)2.22-2.40 (m, 2H) 2.94 (s, 3H) 3.01-3.10 (m, 2H) 3.83 (d, J=12.30 Hz,2H) 4.55 (d, J=8.03 Hz, 2H) 6.50 (s, 1H); LCMS: (MH+)=456 rt=1.09 min.

To a 200 mL round bottomed flask was added tert-butyl4-((2,6-dichloropyrimidin-4-yl)amino)-4-(((methylsulfonyl)oxy)methyl)piperidine-1-carboxylate(2 g, 4.40 mmol) and potassium carbonate (2.43 g, 17.6 mmol) inacetonitrile (80 mL) and water (10 mL). Reaction was stirred at 50° C. 6h. The solution was diluted with water and ethyl acetate, organicsseparated and then washed with brine, dried over magnesium sulfate andevaporated. The residue was dissolved in 10% MeOH/DCM and purified byCombiflash (24 g silica gel column-0-10% MeOH/DCM, 30 min). Fractionswere evaporated to yield tert-butyl7-chloro-5-oxo-3,5-dihydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidine]-1′-carboxylate(344 mg, 23%) as a pale yellow powder.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.43-1.54 (m, 9H) 1.84 (d, J=6.78 Hz, 2H)1.93-2.02 (m, 2H) 3.29-3.42 (m, 2H) 3.73-3.85 (m, 2H) 3.96 (s, 2H) 6.00(s, 1H); LCMS: (MH+)=341 rt=0.66 min.

D257 di-tert-Butyl7-chloro-5-oxo-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidine]-1,1′(3H,5H)-dicarboxylate

To a 100 mL round bottomed flask was added tert-butyl7-chloro-5-oxo-3,5-dihydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidine]-1′-carboxylate(344 mg, 1.01 mmol) in THF (20 mL) and this was cooled in ice andstirred for 15 min. To this was added 60% sodium hydride (202 mg, 5.05mmol) and solution was stirred in ice for 15 min. Boc anhydride (440 mg,2.02 mmol) was added via pipette then stirred for 30 min in ice, thenallowed to warm to RT and stirred 1 h. The mixture was treated withwater and then ethyl acetate and the organics were washed with brine andthen evaporated to a white powder. The powder was triturated withhexanes to yield a white powder (263 mg, 60%).

¹H NMR (400 MHz, CDCl₃) δ ppm 1.42-1.52 (m, 9H) 1.57-1.65 (m, 9H)1.67-1.78 (m, 2H) 2.60-2.85 (m, 4H) 4.11 (s, 2H) 6.77 (s, 1H) LCMS:(MH+)=441 rt=1.04 min.

D258 tert-Butyl7-((3,4-difluorobenzyl)oxy)-5-oxo-3,5-dihydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidine]-1′-carboxylate

To a 25 mL round bottomed flask was added (3,4-difluorophenyl)methanol(102 □mL, 0.895 mmol) in THF (5 mL) and this was cooled in ice andstirred for 15 min. To this was added 60% sodium hydride (120 mg, 2.99mmol) and solution was stirred in ice for 15 min. Solid di-tert-butyl7-chloro-5-oxo-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidine]-1,1′(3H,5H)-dicarboxylate(263 mg, 0.598 mmol) was added, and then stirred for 30 min in ice; thesolution was allowed to warm to RT and stirred 1 h. The mixture wastreated with water and then ethyl acetate, aqueous extracted with ethylacetate, organics combined, washed with brine, dried over magnesiumsulfate and evaporated to an oil. The residue was dissolved in 2 mL ofDMSO and purified by Gilson HPLC (Sunfire C18 column-gradient 10-90%water/acetonitrile over 12 minutes) to yield tert-butyl7-((3,4-difluorobenzyl)oxy)-5-oxo-3,5-dihydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidine]-1′-carboxylate(93 mg, 35%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42 (s, 9H) 1.67 (br. s., 2H) 1.78 (br.s., 2H) 3.30 (br. s., 2H) 3.52 (br. s., 2H) 3.89 (br. s., 2H) 5.28-5.45(m, 3H) 7.33 (br. s., 1H) 7.44-7.64 (m, 2H) 9.51-9.82 (m, 1H); LCMS:(MH+)=449 rt=0.81 min.

D259 4-Amino-1-benzylpiperidine-4-carboxylic Acid

The title compound was synthesized in 2 steps from1-benzylpiperidin-4-one to yield a yellow solid (10.25 g, 81%) (Seeprocedures described in WO2006052722).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25 (d, J=12.80 Hz, 2H) 1.91-2.03 (m,2H) 2.25 (t, J=10.29 Hz, 2H) 2.43-2.50 (m, 2H) 7.19-7.34 (m, 5H); LCMSMH+=235; rt=0.17 min.

D260 (4-Amino-1-benzylpiperidin-4-yl)methanol

To a 200 mL round bottomed flask,4-amino-1-benzylpiperidine-4-carboxylic acid (10.25 g, 43.7 mmol) wasadded to methanol (100 mL) and solution was cooled in ice. To this wasadded thionyl chloride (6.39 mL, 87 mmol) dropwise and solution wasstirred at 0° C. for 1 h then allowed to warm to RT, then heated to 50°C. and stirred over weekend. Solution was filtered and solvent wasevaporated to an oily liquid, which was taken up in sat. Na₂CO₃,extracted with DCM, washed with brine and dried by using MgSO₄ andevaporated to yield methyl 4-amino-1-benzylpiperidine-4-carboxylate(4.21 g, 16.95 mmol, 38.8% yield) as a pale yellow liquid.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.52-1.63 (m, 2H) 2.15 (dt, J=13.36, 6.74Hz, 2H) 2.52 (d, J=4.27 Hz, 4H) 3.54 (s, 2H) 3.74 (s, 3H) 7.18-7.42 (m,5H); LCMS: (MH+)=249 rt=0.26 min.

To a 200 mL round bottom flask was added Lithium aluminum hydride (1.287g, 33.9 mmol) to tetrahydrofuran (45 ml) with steady stirring at 0° C.The addition funnel was charged with a solution of methyl4-amino-1-benzylpiperidine-4-carboxylate (4.21 g, 16.95 mmol) intetrahydrofuran (10 ml) and added, dropwise, to the LAH suspension overthe course of 10 minutes and the reaction was allowed to stir, warmingnaturally to room temperature 2 h. The reaction was then quenched bydropwise addition of 5.7 mL of saturated Na₂SO₄ (recipe=4.4 mLsolution/g LAH). The resulting white precipitate was filtered andsolution evaporated to yield (4-amino-1-benzylpiperidin-4-yl)methanol(2.5 g, 11.35 mmol, 66.9% yield) as an oil.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.39 (d, J=13.55 Hz, 2H) 1.53-1.64 (m, 2H)2.22-2.35 (m, 2H) 2.45-2.56 (m, 2H) 3.29 (s, 2H) 3.47 (s, 2H) 7.14-7.32(m, 5H); LCMS: (MH+)=221 rt=0.16 min.

D261(1-Benzyl-4-((2,6-dichloropyrimidin-4-yl)amino)piperidin-4-yl)methanol

To a 250 ml round bottomed flask was added(4-amino-1-benzylpiperidin-4-yl)methanol (2.5 g, 11.35 mmol) in 25 mL ofTHF at 0° C. To this was added sodium hydride (1.362 g, 34.0 mmol) andsolution was stirred for 30 min. 2,4,6-trichloropyrimidine (1.301 mL,11.35 mmol) dissolved in THF (25 mL) was added dropwise and thenreaction was allowed to warm to RT and stirred overnight. The solutionwas diluted with ethyl acetate and water and the layers were separated,and the aqueous layer was extracted with EtOAc. The combined organiclayers were washed with saturated NaCl, dried (MgSO₄), and concentratedunder reduced pressure. The crude material was purified on aTeledyne-Isco Combiflash Rf purification system. The residue wasdissolved in 10 mL of DCM and injected on a Teledyne-Isco RediSep Rfsilica gel column (40 g) and was eluted with a gradient of ethyl acetateand hexanes (50-100%) over 30 minutes. The appropriate fractions werecollected and evaporated to yield(1-benzyl-4-((2,6-dichloropyrimidin-4-yl)amino)piperidin-4-yl)methanol(732 mg, 1.993 mmol, 17.56% yield) as a white powder.

1H NMR (400 MHz, CD₃OD) δ ppm 1.75 (t, J=10.92 Hz, 2H) 2.32 (d, J=11.04Hz, 4H) 2.71 (d, J=11.80 Hz, 2H) 3.55 (s, 2H) 3.83 (s, 2H) 6.59 (s, 1H)7.24-7.39 (m, 5H); LCMS: (MH+)=368 rt=0.67 min.

D2621′-Benzyl-7-chloro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidin]-5(3H)-one

To a 25 ml round bottomed flask was added(1-benzyl-4-((2,6-dichloropyrimidin-4-yl)amino)piperidin-4-yl)methanol(732 mg, 1.993 mmol) and DIEA (1.044 mL, 5.98 mmol) in THF (10 mL).Solution was cooled to 0° C. and stirred for 30 min. Methanesulfonylchloride (0.186 mL, 2.392 mmol) was added and then reaction was allowedto warm to RT and stirred 3 h, reaction was still not complete, soadditional mesyl chloride (0.186 mL, 2.392 mmol) was added and solutionwas heated to 70° C. overnight. Additional DIEA (2 mL, 12 mmol) wasadded and heated at 70° C. for 2 h. Solution was then diluted with ethylacetate and water, resulting in a brown precipitate which was filteredto yield1′-benzyl-7-chloro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidin]-5(3H)-one(409 mg, 1.236 mmol, 62.0% yield)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.78 (d, J=16.31 Hz, 4H) 2.29 (br. s.,2H) 2.52 (br. s., 2H) 3.80 (br. s., 2H) 5.62 (br. s., 1H) 7.21-7.44 (m,5H) 9.05 (br. s., 1H); LCMS (MH+)=331 rt=0.46 min.

D263 tert-Butyl1′-benzyl-7-chloro-5-oxo-3,5-dihydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidine]-1-carboxylate

To a 25 mL round bottomed flask was added1′-benzyl-7-chloro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidin]-5(3H)-one(408 mg, 1.233 mmol) and DIEA (0.646 mL, 3.70 mmol) in THF (10 mL). Tothis was added DMAP (75 mg, 0.617 mmol) and solution was stirred for 10min. Boc₂O (0.430 mL, 1.850 mmol) was added and solution was stirred for1 h. The solution was diluted with ethyl acetate and water and thelayers were separated, and the aqueous layer was extracted with EtOAc.The combined organic layers were washed with saturated NaCl, dried byusing MgSO₄, and concentrated under reduced pressure to yield tert-butyl1′-benzyl-7-chloro-5-oxo-3,5-dihydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidine]-1-carboxylate(525 mg, 1.218 mmol, 99% yield) as a tan solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.52-1.69 (m, 11H) 1.98 (t, J=11.54 Hz,2H) 2.75 (t, J=12.17 Hz, 2H) 2.84-2.94 (m, 2H) 3.45 (br. s., 2H) 3.95(s, 2H) 6.66 (s, 1H) 7.18-7.28 (m, 5H); LCMS: (MH+)=431, RT=0.73 min.

EXAMPLES E13-((4-Fluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneTrifluoroacetate Salt

To a solution of3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one(30 mg, 0.13 mmol) and (4-fluorophenyl)methanol (16.8 mg, 0.13 mmol) inDMF (1 mL) was added sodium hydride (10.6 mg, 0.27 mmol). The reactionmixture was stirred at rt for 30 min., then quenched with water. Directpurification via MDAP afforded the title product of TFA salt (25 mg,43.8%) as a white solid.

¹H NMR (400 MHz, CDCl₃): δ 7.38 (m, 2H), 7.04 (m, 2H), 5.30 (s, 2H),5.27 (s, 1H), 4.27 (t, 1H), 3.97-3.88 (m, 2H), 3.69 (m, 2H), 3.08 (m,1H), 2.01 (m, 2H), 1.82 (m, 1H), 1.57-1.49 (m, 3H).

E23-((3,4,5-Trifluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand (3,4,5-trifluorophenyl)methanol.

LCMS (ESI): m/z 352 [M+H]⁺; 2.33 min (ret time).

E33-((3,5-Difluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo-[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from (3,5-difluorophenyl)methanol and3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido-[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 334 [M+H]⁺; 1.37 min (ret time)

E44-(((1-Oxo-6,7,8,9,9a,10-Hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E1 starting from 4-(hydroxymethyl)benzonitrile and3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido-[1′,2′:3,4]imida-zo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 323 [M+H]⁺; 1.30 min (ret time)

E53-((3,4-Difluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from (3,4-difluorophenyl)methanol and3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido-[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 334 [M+H]⁺; 1.21 min (ret time).

E63-(((1-Oxo-6,7,8,9,9a,1-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E1 starting from3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand 3-(hydr-oxymethyl)benzonitrile.

LC-MS (ESI): m/z 323 [M+H]⁺; 1.30 min (ret time)

E73-((3-Chloro-4-(trifluoromethyl)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido-[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand (3-chloro-4-(trifluoromethyl)phenyl)methanol

LC-MS (ESI): m/z 400 [M+H]⁺; 1.49 min (ret time)

E83-((2,4-Difluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido-[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand (2,4-difluorophenyl)methanol.

LC-MS (ESI): m/z 334[M+H]⁺; 2.14 min (ret time).

E93-((4-Methylbenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand p-tolyl-methanol.

LCMS (ESI): m/z 312 [M+H]⁺; 2.28 min (ret time)

E105-(((1-Oxo-6,7,8,9,9a,1-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)-2-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E1 starting from3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand5-(hydroxymethyl)-2-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzonitrile.

LCMS (ESI): m/z 484 [M+H]⁺; 2.63 min (ret time).

E112-Chloro-5-(2-fluoro-4-(((1-oxo-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)phenoxy)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E1 starting from 2-chloro-5-(2-fluoro-4-(hydroxymethyl)phenoxy)benzonitrile and3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LCMS (ESI): m/z 467 [M+H]⁺; 2.80 min (ret time).

E125-(((1-Oxo-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)-2-(3-(trifluoromethyl)phenoxy)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E1 starting from5-(hydroxymethyl)-2-(3-(trifluoromethyl)phenoxy)benzonitrile and3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LCMS (ESI): m/z 483 [M+H]⁺; 2.95 min (ret time)

E133-((4-Fluoro-3-(trifluoromethyl)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido-[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from (4-fluoro-3-(trifluoromethyl)phenyl)methanol and3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido-[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LCMS (ESI): m/z 384 [M+H]⁺; 2.52 min (ret time).

E14 3-((3,4-Difluoro-5-methylbenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1Hpyrido[1′,2′:3,4]imidazo-[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from (3,4-difluoro-5-methylphenyl)methanol and3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido-[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LCMS (ESI): m/z 348 [M+H]⁺; 2.40 min (ret time)

E153-Fluoro-5-(((1-oxo-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E1 starting from 3-fluoro-5-(hydroxymethyl)benzonitrile and3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]-imidazo[1,2-c]pyrimidin-1-one.

LCMS (ESI): m/z 341 [M+H]⁺; 2.09 min (ret time).

E163-((3-Chloro-4,5-difluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from (3-chloro-4,5-difluorophenyl)methanol and3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]i-midazo[1,2-c]pyrimidin-1-one.

LCMS (ESI): m/z 368 [M+H]⁺; 2.52 min (ret time)

E173-((3-Fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol and3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido [1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 477 [M+H]⁺; 1.99 min (ret time).

E183-((4-(3,4-Difluorophenoxy)-3-fluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand (4-(3,4-difluorophenoxy)-3-fluorophenyl)methanol.

LCMS (ESI): m/z 444 [M+H]⁺; 2.88 min (ret time).

E192-(3,4-Difluorophenoxy)-5-(((1-oxo-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo-[1,2-c]pyrimidin-3-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E1 starting from3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand 2-(3,4-difluorophenoxy)-5-(hydroxymethyl)benzonitrile.

LCMS (ESI): m/z 451 [M+H]⁺; 2.73 min (ret time).

E202-Chloro-4-(2-cyano-4-(((1-oxo-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)phenoxy)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E1 starting from3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand 2-chloro-4-(2-cyano-4-(hydroxymethyl)phenoxy)benzonitrile.

LCMS (ESI): m/z 474 [M+H]⁺; 2.70 min (ret time)

E213-((3,5-Difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand(3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol.

LCMS (ESI): m/z 495 [M+H]⁺; 2.78 min (ret time)

E223-((3-Fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and3-chloro-6,7,8,9,9a,10-hexa-hydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 477 [M+H]⁺; 1.04 min (ret time).

E235-(((1-Oxo-6,7,8,9,9a,1-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)-2-(4-(trifluoromethyl)phenoxy)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E1 starting from3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand 5-(hydr-oxymethyl)-2-(4-(trifluoromethyl)phenoxy)benzonitrile.

LCMS (ESI): m/z 483 [M+H]⁺; 2.90 min (ret time).

E24 2-(4-Chloro-3-fluorophenoxy)-5-(((1-oxo-6,7,8,9,9a,10-hexahydro-1Hpyrido-[1′,2′:3,4]imi-dazo[1,2-c]pyrimidin-3-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E1 starting from3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand 2-(4-chloro-3-fluorophenoxy)-5-(hydroxym-ethyl)benzonitrile.

LCMS (ESI): m/z 467 [M+H]⁺; 2.85 min (ret time).

E253-((3,5-Difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanoland 3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido [1′,2′:3,4] imidazo[1,2-c] pyrimidin-1-one.

LC-MS (ESI): m/z 495 [M+H]⁺; 1.07 min (ret time).

E263-((4-((2-Chloropyridin-4-yl)oxy)-3,5-difluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand (4-((2-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)methanol.

LCMS (ESI): m/z 461 [M+H]⁺; 2.58 min (ret time).

E273-((3-Chloro-4-fluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand (3-chlo-ro-4-fluorophenyl)methanol.

LCMS (ESI): m/z 350 [M+H]⁺; 2.36 min (ret time).

E283-(2-Fluoro-4-(((1-oxo-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)phenoxy)-5-(trifluoromethyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E1 starting from3-(2-fluoro-4-(hydroxymethyl)phenoxy)-5-(trifluoromethyl)benzonitrileand3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LCMS (ESI): m/z 501 [M+H]⁺; 2.91 min (ret time).

E293-((3-Chloro-5-fluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand (3-chlo-ro-5-fluorophenyl)methanol.

LCMS (ESI): m/z 350 [M+H]⁺; 2.42 min (ret time).

E30(R)-3-((3,4-Difluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imida-zo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(R)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand (3,4-difluorophenyl)methanol.

LCMS (ESI): m/z 334 [M+H]⁺; 2.29 min (ret time).

E31(S)-3-((3,4-Difluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(S)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand (3,4-difluorophenyl)methanol.

LCMS (ESI): m/z 334 [M+H]⁺; 2.23 min (ret time)

E32(S)-3-((3,4,5-Trifluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(S)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand (3,4,5-trifluorophenyl)methanol.

LCMS (ESI): m/z 352 [M+H]⁺; 2.37 min (ret time)

E33(S)-3-(((1-Oxo-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E1 starting from(S)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand 3-(hydroxymethyl)benzonitrile.

LCMS (ESI): m/z 323 [M+H]⁺; 2.40 min (ret time).

E34(S)-3-((4-Fluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo-[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(S)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand (4-fluorophenyl)methanol.

LCMS (ESI): m/z 316 [M+H]⁺; 2.31 min (ret time).

E35(S)-3-((3,5-Difluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(S)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand (3,5-difluorophenyl)methanol.

LCMS (ESI): m/z 334 [M+H]⁺; 2.76 min (ret time).

E36(S)-3-(2-(Thiophen-2-yl)ethoxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(S)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand 2-(thiophen-2-yl)ethanol.

LCMS (ESI): m/z 318 [M+H]⁺; 2.69 min (ret time).

E373-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanoland 3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 495 [M+H]⁺; 2.04 min (ret time).

E383-((3-Fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and3-chloro-6,7,8,9,9a,10-hexa-hydro-1H-pyrido [1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 477 [M+H]⁺; 1.04 min (ret time).

E393-((3,5-Difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanoland3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 495 [M+H]⁺; 1.07 min (ret time).

E40(S)-3-((3-Fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol and(S)-3-chloro-6,7,8,9,9a,10-hex-ahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 477 [M+H]⁺; 1.03 min(ret time).

E413-((4-Fluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanoland 3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 495 [M+H]⁺; 1.05 min (ret time).

E42(S)-3-((3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and(S)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 477[M+H]⁺; 1.03 min (ret time).

E433-((3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol and3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 478 [M+H]⁺; 1.24 min (ret time).

E443-((3-Fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from3-fluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol and3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido-[1′,2′:3,4]imida-zo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 477 [M+H]⁺; 1.99 min (ret time).

E453-((3,5-Difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanoland3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 495 [M+H]⁺; 1.06 min (ret time).

E463-((3-Fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol and3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 478 [M+H]⁺; 2.00 min (ret time).

E473-((3-Fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(3-fluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 477 [M+H]⁺; 1.99 min (ret time).

E483-((3-Fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 477 [M+H]⁺; 1.08 min (ret time).

E493-((3,5-Fifluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanoland3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LCMS (ESI): m/z 495 [M+H]⁺; 1.10 min (ret time).

E50(S)-3-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)methanol and(S)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

LCMS (ESI): m/z 430 [M+H]⁺; 1.34 min (ret time).

E51(S)-3-((3-fluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(3-fluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)methanol and(S)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

LCMS (ESI): m/z 412 [M+H]⁺; 1.15 min (ret time).

E52(R)-3-((3-Fluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(R)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand (3-fluorophenyl)methanol.

LCMS (ESI): m/z 316 [M+H]⁺; 3.83 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.34-7.26 (m, 1H), 7.17-7.11 (m, 2H),7.02-6.97 (m, 1H), 5.39 (s, 2H), 4.99 (s, 1H), 4.24-4.19 (m, 1H),3.77-3.64 (m, 2H), 3.55-3.51 (m, 1H), 3.02-2.97 (m, 1H), 2.01-1.92 (m,2H), 1.76 (d, J=5.7 Hz, 1H), 1.61-1.45 (m, 3H).

E53(R)-3-((3,5-Difluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(R)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand (3,5-difluorophenyl)methanol.

LCMS (ESI): m/z 334 [M+H]⁺; 3.97 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 6.91 (d, J=4.5 Hz, 2H), 6.75-6.71 (m, 1H),5.37 (s, 2H), 5.00 (s, 1H), 4.24-4.19 (m, 1H), 3.78-3.76 (m, 1H),3.69-3.65 (m, 1H), 3.56-3.53 (m, 1H), 3.04-3.00.

E54(R)-3-((3,4,5-Trifluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(R)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand (3,4,5-trifluorophenyl)methanol.

LCMS (ESI): m/z 352 [M+H]⁺; 4.10 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.02 (t, J=5.4 Hz, 1H), 5.32 (s, 2H), 4.98(s, 1H), 4.24-4.19 (m, 1H), 3.79-3.75 (m, 1H), 3.69-3.64 (m, 1H),3.56-3.52 (m, 1H), 3.04-2.97 (m, 1H), 1.95 (d, J=8.1 Hz, 2H), 1.78-1.76(m, 1H), 1.57-1.48 (m, 3H).

E55(R)-3-((2,4-Difluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(R)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand (2,4-difluorophenyl)methanol.

LCMS (ESI): m/z 334 [M+H]⁺; 3.88 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.49-7.43 (m, 1H), 6.88-6.79 (m, 1H), 5.40(s, 2H), 4.95 (s, 1H), 4.24-4.19 (m, 1H), 3.77-3.72 (m, 1H), 3.69-3.64(m, 1H), 3.51 (t, J=7.2 Hz, 1H), 2.99 (t, J=7.5 Hz, 1H), 2.01-1.93 (m,2H), 1.76-1.73 (m, 1H), 1.59-1.46 (m, 3H).

E56(R)-3-((2,3-Difluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(R)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand (2,3-difluorophenyl)methanol.

LCMS (ESI): m/z 334 [M+H]⁺; 3.88 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.26-7.21 (m, 1H), 7.14-7.05 (m, 2H), 5.47(s, 2H), 4.97 (s, 1H), 4.24-4.19 (m, 1H), 3.77-3.53 (m, 2H), 3.51 (t,J=9.6 Hz, 1H), 3.03-2.96 (m, 1H), 1.96 (t, J=9.0 Hz, 2H), 1.75 (d, J=3.6Hz, 1H), 1.60-1.43 (m, 3H).

E57(S)-3-((2,4-Difluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(S)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand (2,4-difluorophenyl)methanol.

LCMS (ESI): m/z 334 [M+H]⁺; 3.30 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.46-7.43 (m, 1H), 6.87-6.77 (m, 2H), 5.38(s, 2H), 4.94 (s, 1H), 4.23-4.16 (m, 1H), 3.76-3.61 (m, 2H), 3.51-3.46(m, 1H), 2.98 (d, J=3.0 Hz, 1H), 2.02-1.44 (m, 6H).

E58(S)-3-((2,3-Difluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(S)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand (2,3-difluorophenyl)methanol.

LCMS (ESI): m/z 334 [M+H]⁺; 3.89 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.28-7.05 (m, 3H), 5.46 (s, 2H), 4.97 (s,1H), 4.24-4.18 (m, 1H), 3.78-3.49 (m, 3H), 2.99 (d, J=2.7 Hz, 1H),1.96-1.45 (m, 6H).

E59(S)-3-((2,4,5-Trifluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(S)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand (2,4,5-trifluorophenyl)methanol.

LCMS (ESI): m/z 352 [M+H]⁺; 4.00 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.33-7.27 (m, 1H), 6.97-6.88 (m, 1H), 5.39(s, 2H), 4.97 (m, 1H), 4.25-4.18 (m, 1H), 3.76-3.50 (m, 3H), 3.01-3.00(m, 1H), 1.97-1.93 (m, 2H), 1.77-1.75 (m, 2H), 1.52-1.46 (m, 3H).

E60(S)-3-((3-Fluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(S)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-oneand (3-fluorophenyl)methanol.

LCMS (ESI): m/z 316 [M+H]⁺; 3.83 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.32-7.27 (m, 1H), 7.17-7.09 (m, 2H), 6.98(d, J=1.8 Hz, 1H), 5.38 (s, 2H), 4.99 (s, 1H), 4.24-4.17 (m, 1H),3.74-3.62 (m, 2H), 3.54-3.50 (m, 1H), 3.01-2.98 (m, 1H), 1.95-1.91 (m,3H), 1.73 (s, 1H), 1.51-1.45 (m, 3H).

E61(S)-3-((2,4-Difluorobenzyl)(methyl)amino)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

To a solution of(S)-3-((2,4-difluorobenzyl)amino)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one(64.0 mg, 0.193 mmol) and K₂CO₃ (133 mg, 0.965 mmol) in DMF (3 mL) wasadded CH₃I (137 mg, 0.965 mmol) at room temperature. The mixture wasstirred at room temperature overnight. To the reaction mixture was addedwater (10 mL), extracted with EtOAc (30 mL×3), washed with brine (10mL), dried over Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified with prep-HPLC to give the titlecompound (39 mg, 59%) as a pale yellow solid.

LCMS (ESI): m/z 347 [M+H]⁺; 3.11 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.61-7.58 (m, 1H), 6.88-6.73 (m, 2H), 4.63(s, 1H), 4.36 (s, 2H), 4.12-4.04 (m, 1H), 3.56-3.45 (m, 3H), 3.41 (s,3H), 2.92-2.88 (m, 1H), 1.97-1.90 (m, 2H), 1.76-1.60 (m, 1H), 1.56-1.36(m, 3H).

E62(R)-3-((3,5-Difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)phenyl)methanol and(R)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LCMS (ESI): m/z 436 [M+H]⁺; 4.48 min (ret time).

¹H NMR (400 MHz, CDCl₃): δ 6.97-6.92 (m, 2H), 5.31 (s, 2H), 4.98 (s,1H), 4.84 (t, J=6.0 Hz, 1H), 4.73 (t, J=6.0 Hz, 1H), 4.24-4.19 (m, 1H),3.79-3.74 (m, 1H), 3.69-3.64 (m, 1H), 3.55-3.52 (m, 1H), 3.03-2.97 (m,1H), 2.18-2.15 (m, 1H), 2.11 (t, J=6.4 Hz, 1H), 1.97-1.93 (m, 2H),1.78-1.75 (m, 1H), 1.54-1.45 (m, 3H), 1.09 (t, J=6.8 Hz, 2H), 0.67-0.64(m, 2H).

E63 3-((3, 5-Difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-7,8,8a, 9-tetrahydro pyrrolo [1′, 2′:3, 4] imidazo [1, 2-c]pyrimidin-1(6H)-one

To the solution of3-chloro-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one(85 mg, 0.402 mmol) and(3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)methanol (96 mg,0.402 mmol) in N,N-dimethylformamide (10 mL), sodium hydride (48.2 mg,1.205 mmol) was added at 0° C. and stirred further 10 min. The resultmixture was quenched and purified via C-18 flash column, removed thesolvent afforded white solid of3-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one(55 mg, 0.126 mmol, 31.3% yield).

LC-MS (ESI): m/z 416 [M+H]⁺; 3.55 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.61 (s, 1H), 7.32-7.27 (m, 3H), 5.34 (s,1H), 5.30-5.23 (q, 2H), 4.10-4.01 (m, 2H), 3.89-3.85 (m, 1H), 3.73 (s,3H), 3.40-3.28 (m, 2H), 2.03-1.87 (m, 3H), 1.49-1.42 (m, 1H).

E64 3-((4-((1-Ethyl-1H-pyrazol-4-yl) oxy)-3, 5-difluorobenzyl) oxy)-7,8, 8a, 9-tetrahydropyrrolo [1′, 2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from3-chloro-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-oneand (4-((1-ethyl-1H-pyrazol-4-yl)oxy)-3,5-difluorophenyl) methanol.

LC-MS (ESI): m/z 430 [M+H]⁺; 3.71 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.66 (s, 1H), 7.38-7.28 (m, 3H), 5.34 (s,1H), 5.30-5.23 (q, 2H), 4.07-3.99 (m, 4H), 3.88-3.85 (m, 1H), 3.35-3.28(m, 2H), 2.08-1.89 (m, 3H), 1.49-1.39 (m, 1H), 1.33-1.23 (t, 3H).

E65 3-((3, 5-Difluoro-4-((1-isopropyl-1H-pyrazol-4-yl) oxy) benzyl)oxy)-7, 8, 8a, 9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from3-chloro-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-oneand (3,5-difluoro-4-((1-isopropyl-1H-pyrazol-4-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 444 [M+H]⁺; 2.56 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.69 (s, 1H), 7.32-7.26 (m, 3H), 5.34 (s,1H), 5.30-5.23 (q, 2H), 4.40-4.34 (m, 1H), 4.09-4.01 (m, 2H), 3.89-3.83(m, 1H), 3.31-3.28 (m, 2H), 2.03-1.86 (m, 3H), 1.49-1.39 (m, 1H),1.36-1.34 (d, 6H).

E66 (R)-3-((3, 5-difluoro-4-((1-methyl-1H-pyrazol-4-yl) oxy) benzyl)oxy)-7, 8, 8a, 9-tetrahydro pyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (R)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 416 [M+H]⁺; 2.28 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.61 (s, 1H), 7.32-7.27 (m, 3H), 5.34 (s,1H), 5.30-5.23 (q, 2H), 4.10-4.01 (m, 2H), 3.89-3.85 (m, 1H), 3.73 (s,3H), 3.40-3.28 (m, 2H), 2.03-1.87 (m, 3H), 1.49-1.42 (m, 1H).

E67 (R)-3-((3, 5-difluoro-4-((2-(trifluoromethyl) pyridin-4-yl) oxy)benzyl) oxy)-7, 8, 8a, 9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

To a solution of(R)-3-chloro-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one(85 mg, 0.402 mmol) and(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol(123 mg, 0.402 mmol) in DMF (10 mL) was added sodium hydride (48.2 mg,1.205 mmol) at 0° C. and stirred for 10 min. The reaction mixture wasquenched and purification via C-18 flash column afforded the titlecompound (50 mg, 0.099 mmol, 24.62% yield) as a white.

LC-MS (ESI): m/z 481 [M+H]⁺; 2.83 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 8.70-8.68 (d, 1H), 7.67-7.66 (d, 1H),7.47-7.45 (d, 2H), 7.33-7.31 (dd, 1H), 5.37 (s, 1H), 5.37-5.30 (q, 2H),4.10-4.02 (m, 2H), 3.90-3.84 (m, 1H), 3.33-3.27 (m, 2H), 2.04-1.85 (m,3H), 1.50-1.42 (m, 1H).

¹⁹F NMR (376 MHz, DMSO-d₆): δ (ppm): −66.65, −126.83.

E68 (R)-3-((3-fluoro-4-((1-methyl-H-pyrazol-4-yl) oxy) benzyl) oxy)-7,8, 8a, 9-tetrahydro pyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (R)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3-fluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 398 [M+H]⁺; 2.28 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.76 (s, 1H), 7.40-7.36 (m, 2H), 7.19-7.17(d, 1H), 7.09-7.05 (t, 1H), 5.29 (s, 1H), 5.25-5.18 (q, 2H), 4.08-4.00(m, 2H), 3.89-3.82 (m, 1H), 3.80 (s, 3H), 3.30-3.25 (m, 2H), 2.03-1.83(m, 3H), 1.48-1.41 (m, 1H).

E69 (R)-3-((3-fluoro-4-((2-(trifluoromethyl) pyrimidin-5-yl) oxy)benzyl) oxy)-7, 8, 8a, 9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (R)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 464 [M+H]⁺; 2.71 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 8.89 (s, 2H), 7.56-7.47 (m, 2H), 7.36-7.34(d, 1H), 5.34 (s, 1H), 5.35-5.28 (q, 2H), 4.07-4.01 (m, 2H), 3.90-3.84(m, 1H), 3.33-3.27 (m, 2H), 2.08-1.84 (m, 3H), 1.49-1.39 (m, 1H).

E70(R)-3-((3,4,5-trifluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (R)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3,4,5-trifluorophenyl)methanol.

LC-MS (ESI): m/z 338 [M+H]⁺; 2.37 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.41-7.37 (m, 2H), 5.34 (s, 1H), 5.30-5.23(s, 2H), 4.09-4.03 (m, 2H), 3.89-3.83 (m, 1H), 3.40-3.28 (m, 2H),2.20-1.97 (m, 3H), 1.52-1.42 (m, 1H).

E71 (S)-3-((3, 5-difluoro-4-((2-(trifluoromethyl) pyridin-4-yl) oxy)benzyl) oxy)-7, 8, 8a, 9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor 3-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro pyrrolo [1′, 2′:3, 4] imidazo [1, 2-c] pyrimidin-1(6H)-onestarting from (S)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 481 [M+H]⁺; 3.04 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 8.70-8.68 (d, 1H), 7.68-7.67 (d, 1H),7.47-7.45 (d, 2H), 7.33-7.31 (dd, 1H), 5.37 (s, 2H), 5.33 (s, 1H),4.08-4.02 (m, 2H), 3.889-3.86 (m, 1H), 3.33-3.27 (m, 2H), 2.04-1.85 (m,3H), 1.50-1.45 (m, 1H).

An exemplary process is provided: to a solution of(S)-3-chloro-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one(57 mg, 0.269 mmol) and(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol(82 mg, 0.269 mmol) in DMF (10 mL) was added sodium hydride (32.3 mg,0.808 mmol) at 0° C. and stirred for 10 min. The reaction mixture wasquenched and purification via C-18 flash column afforded the titlecompound (45.8 mg, 0.091 mmol, 33.6% yield) as a white solid.

LC-MS (ESI): m/z 481 [M+H]⁺; 3.04 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 8.70-8.68 (d, 1H), 7.68-7.67 (d, 1H),7.47-7.45 (d, 2H), 7.33-7.31 (dd, 1H), 5.37 (s, 2H), 5.33 (s, 1H),4.08-4.02 (m, 2H), 3.88-3.86 (m, 1H), 3.31-3.29 (m, 2H), 2.04-1.85 (m,3H), 1.50-1.45 (m, 1H).

¹⁹F NMR (376 MHz, DMSO-d₆): δ (ppm): −66.62, −126.82.

E72 (S)-3-((3-fluoro-4-((2-(trifluoromethyl) pyrimidin-5-yl) oxy)benzyl) oxy)-7, 8, 8a, 9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (R)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 464 [M+H]⁺; 2.89 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 8.89 (s, 2H), 7.55-7.47 (m, 2H), 7.36-7.34(d, 1H), 5.34 (s, 1H), 5.35-5.28 (q, 2H), 4.07-4.01 (m, 2H), 3.90-3.84(m, 1H), 3.33-3.28 (m, 2H), 2.04-1.87 (m, 3H), 1.47-1.42 (m, 1H).

E73(S)-3-((3,4,5-trifluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrol[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (S)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3,4,5-trifluorophenyl)methanol.

LC-MS (ESI): m/z 338 [M+H]⁺; 2.37 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.41-7.37 (m, 2H), 5.34 (s, 1H), 5.30-5.23(s, 2H), 4.09-4.03 (m, 2H), 3.89-3.83 (m, 1H), 3.40-3.28 (m, 2H),2.20-1.97 (m, 3H), 1.52-1.42 (m, 1H).

E74(S)-3-((4-(3,4-difluorophenoxy)-3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (S)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(4-(3,4-difluorophenoxy)-3,5-difluorophenyl)methanol.

LC-MS (ESI): m/z 448 [M+H]⁺; 2.98 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.58-7.41 (m, 3H), 7.28-7.23 (m, 1H),6.82-6.80 (m, 1H), 5.36 (s, 1H), 5.31-5.27 (q, 2H), 4.08-4.01 (m, 2H),3.88-3.86 (m, 1H), 3.38-3.28 (m, 2H), 2.02-1.76 (m, 3H), 1.47-1.44 (m,1H).

E75 3-((3, 5-difluoro-4-((2-(trifluoromethyl) pyridin-4-yl) oxy) benzyl)oxy)-7, 8, 8a, 9-tetrahydro pyrrolo [1′, 2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from 3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 481 [M+H]⁺; 2.83 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 8.70-8.68 (d, 1H), 7.68-7.66 (d, 1H),7.47-7.45 (d, 2H), 7.33-7.31 (dd, 1H), 5.37 (s, 1H), 5.37-5.30 (q, 2H),4.10-4.02 (m, 2H), 3.90-3.84 (m, 1H), 3.33-3.27 (m, 2H), 2.04-1.85 (m,3H), 1.50-1.42 (m, 1H).

E763-((6-(4-Chloro-3-(trifluoromethyl)phenoxy)-5-fluoropyridin-3-yl)methoxy)-7,8,8a,9tetra hydro pyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from 3-chloro-7, 8, 8a, 9-tetrahydropyrrolo[1′, 2′:3,4] imidazo[1, 2-c]pyrimidin-1(6H)-one and(6-(4-chloro-3-(trifluoromethyl)phenoxy)-5-fluoropyridin-3-yl)methanol.

LC-MS (ESI): m/z 498 [M+H]⁺; 3.14 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 8.04-7.98 (m, 2H), 7.82-7.80 (m, 1H),7.62-7.60 (q, 1H), 7.33-7.31 (dd, 1H), 5.28 (s, 1H), 5.31-5.23 (q, 2H),4.06-4.00 (m, 2H), 3.89-3.86 (m, 1H), 3.26-3.26 (m, 2H), 2.02-1.86 (m,3H), 1.45-1.40 (m, 1H).

E772-(4-Chloro-3-(trifluoromethyl)phenoxy)-5-(((1-oxo-1,6,7,8,8a,9-hexahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E63 starting from 3-chloro-7, 8, 8a, 9-tetrahydropyrrolo[1′, 2′:3,4] imidazo[1, 2-c]pyrimidin-1(6H)-one and2-(4-chloro-3-(trifluoromethyl)phenoxy)-5-(hydroxymethyl)benzonitrile.

LC-MS (ESI): m/z 503 [M+H]⁺; 3.34 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 8.03-8.02 (d, 1H), 7.84-7.82 (d, 1H),7.77-7.74 (m, 2H), 7.54-7.51 (m, 1H), 7.20-7.18 (d, 1H), 5.64 (s, 1H),5.37-5.30 (q, 2H), 4.21-4.09 (m, 2H), 3.92-3.88 (m, 1H), 3.40-3.36 (m,2H), 2.08-1.96 (m, 3H), 1.57-1.47 (m, 1H).

E783-((3,5-Difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from 3-chloro-7, 8, 8a, 9-tetrahydropyrrolo[1′, 2′:3,4] imidazo[1, 2-c]pyrimidin-1(6H)-one and(3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol,

LC-MS (ESI): m/z 481 [M+H]⁺; 3.09 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 8.70-8.69 (d, 1H), 7.92-7.90 (d, 1H),7.65-7.62 (dd, 1H), 7.46-7.44 (d, 2H), 5.37 (s, 1H), 5.37-5.29 (q, 2H),4.08-3.90 (m, 2H), 3.88-3.86 (m, 1H), 3.32-3.29 (m, 2H), 2.06-1.85 (m,3H), 1.47-1.42 (m, 1H).

E79(R)-3-((3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (R)-3-chloro-7, 8, 8a, 9-tetrahydropyrrolo[1′,2′:3, 4] imidazo[1, 2-c]pyrimidin-1(6H)-one and(3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 481 [M+H]⁺; 3.08 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 8.70-8.69 (d, 1H), 7.92-7.90 (d, 1H),7.65-7.62 (dd, 1H), 7.46-7.44 (d, 2H), 5.37 (s, 1H), 5.37-5.29 (q, 2H),4.08-3.90 (m, 2H), 3.88-3.86 (m, 1H), 3.32-3.29 (m, 2H), 2.05-1.85 (m,3H), 1.49-1.42 (m, 1H).

E80(S)-3-((3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (S)-3-chloro-7, 8, 8a, 9-tetrahydropyrrolo[1′,2′:3, 4] imidazo[1, 2-c]pyrimidin-1(6H)-one and(3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol,

LC-MS (ESI): m/z 481 [M+H]⁺; 3.08 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 8.70-8.69 (d, 1H), 7.92-7.90 (d, 1H),7.65-7.62 (dd, 1H), 7.46-7.44 (d, 2H), 5.37 (s, 1H), 5.37-5.29 (q, 2H),4.08-3.90 (m, 2H), 3.88-3.86 (m, 1H), 3.32-3.29 (m, 2H), 2.05-1.85 (m,3H), 1.49-1.42 (m, 1H).

E813-((3,5-difluoro-4-(3-(trifluoromethyl)phenoxy)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3, 4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from 3-chloro-7, 8, 8a, 9-tetrahydropyrrolo[1′, 2′:3,4] imidazo [1, 2-c]pyrimidin-1(6H)-one and (3,5-difluoro-4-(3-(trifluoromethyl)phenoxy)phenyl)methanol.

LC-MS (ESI): m/z 480 [M+H]⁺; 3.43 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.64-7.60 (t, 1H), 7.53-7.51 (d, 1H),7.43-7.37 (m, 3H), 7.28-7.26 (m, 1H), 5.37 (s, 1H), 5.35-5.28 (q, 2H),4.08-4.02 (m, 2H), 3.88-3.86 (m, 1H), 3.32-3.29 (m, 2H), 2.04-1.88 (m,3H), 1.47-1.42 (m, 1H).

E823-((6-(4-fluoro-3-(trifluoromethyl)phenoxy)pyridin-3-yl)methoxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from 3-chloro-7, 8, 8a, 9-tetrahydropyrrolo[1′, 2′:3,4] imidazo [1, 2-c]pyrimidin-1(6H)-one and(6-(4-fluoro-3-(trifluoromethyl)phenoxy)pyridin-3-yl)methanol.

LC-MS (ESI): m/z 463 [M+H]⁺; 2.86 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 8.20-8.20 (d, 1H), 7.97-7.96 (d, 1H),7.95-7.56 (m, 3H), 7.16-7.14 (d, 1H), 5.27 (s, 1H), 5.29-5.21 (q, 2H),4.06-4.00 (m, 2H), 3.87-3.85 (m, 1H), 3.32-3.26 (m, 2H), 2.01-1.86 (m,3H), 1.45-1.42 (m, 1H).

E83(S)-3-((3,5-difluoro-4-(3-(trifluoromethyl)phenoxy)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3, 4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (S)-3-chloro-7, 8, 8a, 9-tetrahydropyrrolo[1′,2′:3, 4] imidazo [1, 2-c]pyrimidin-1(6H)-one and (3,5-difluoro-4-(3-(trifluoromethyl)phenoxy)phenyl)methanol.

LC-MS (ESI): m/z 480 [M+H]⁺; 3.17 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.64-7.60 (t, 1H), 7.53-7.51 (d, 1H),7.43-7.37 (m, 3H), 7.28-7.26 (m, 1H), 5.37 (s, 1H), 5.35-5.28 (q, 2H),4.08-4.02 (m, 2H), 3.88-3.86 (m, 1H), 3.32-3.29 (m, 2H), 2.04-1.88 (m,3H), 1.47-1.42 (m, 1H).

E84(S)-3-((6-(4-fluoro-3-(trifluoromethyl)phenoxy)pyridin-3-yl)methoxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (S)-3-chloro-7, 8, 8a, 9-tetrahydropyrrolo[1′,2′:3, 4] imidazo [1, 2-c]pyrimidin-1(6H)-one and(6-(4-fluoro-3-(trifluoromethyl)phenoxy)pyridin-3-yl)methanol.

LC-MS (ESI): m/z 463 [M+H]⁺; 2.86 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 8.20-8.20 (d, 1H), 7.97-7.96 (d, 1H),7.95-7.56 (m, 3H), 7.16-7.14 (d, 1H), 5.27 (s, 1H), 5.29-5.21 (q, 2H),4.06-4.00 (m, 2H), 3.87-3.85 (m, 1H), 3.32-3.26 (m, 2H), 2.01-1.86 (m,3H), 1.45-1.42 (m, 1H).

E852-(3-fluorophenoxy)-5-(((1-oxo-1,6,7,8,8a,9-hexahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E63 starting from 3-chloro-7, 8, 8a, 9-tetrahydropyrrolo[1′, 2′:3,4] imidazo[1, 2-c]pyrimidin-1(6H)-one and2-(3-fluorophenoxy)-5-(hydroxymethyl)benzonitrile.

LC-MS (ESI): m/z 419 [M+H]⁺; 2.89 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.97-7.96 (d, 1H), 7.74-7.71 (m, 1H),7.53-7.47 (q, 1H), 7.14-7.09 (m, 3H), 7.00-6.98 (m, 1H), 5.32 (s, 1H),5.32-5.24 (q, 2H), 4.06-4.00 (m, 2H), 3.89-3.83 (m, 1H), 3.30-3.25 (m,2H), 2.04-1.81 (m, 3H), 1.48-1.38 (m, 1H).

E86(S)-2-(3-fluorophenoxy)-5-(((1-oxo-1,6,7,8,8a,9-hexahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E63 starting from (S)-3-chloro-7, 8, 8a, 9-tetrahydropyrrolo[1′,2′:3, 4] imidazo[1, 2-c]pyrimidin-1(6H)-one and2-(3-fluorophenoxy)-5-(hydroxymethyl)benzonitrile.

LC-MS (ESI): m/z 419 [M+H]⁺; 2.89 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.97-7.96 (d, 1H), 7.74-7.72 (m, 1H),7.53-7.48 (q, 1H), 7.15-7.09 (m, 3H), 7.00-6.98 (m, 1H), 5.32 (s, 1H),5.32-5.24 (q, 2H), 4.09-4.01 (m, 2H), 3.89-3.83 (m, 1H), 3.31-3.25 (m,2H), 2.04-1.82 (m, 3H), 1.48-1.38 (m, 1H).

E872-(3,5-Difluorophenoxy)-5-(((1-oxo-1,6,7,8,8a,9-hexahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E63 starting from 3-chloro-7, 8, 8a, 9-tetrahydropyrrolo[1′, 2′:3,4] imidazo[1, 2-c]pyrimidin-1(6H)-one and2-(3,5-difluorophenoxy)-5-(hydroxymethyl)benzonitrile.

LC-MS (ESI): m/z 437 [M+H]⁺; 2.96 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.95-7.95 (d, 1H), 7.72-7.69 (dd, 1H),7.59-7.47 (m, 2H), 7.09-7.04 (m, 2H), 5.31 (s, 1H), 5.31-5.23 (q, 2H),4.09-4.00 (m, 2H), 3.89-3.83 (m, 1H), 3.31-3.25 (m, 2H), 2.05-1.81 (m,3H), 1.48-1.38 (m, 1H).

E88(S)-2-(3,5-difluorophenoxy)-5-(((1-oxo-1,6,7,8,8a,9-hexahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E63 starting from (S)-3-chloro-7, 8, 8a, 9-tetrahydropyrrolo[1′,2′:3, 4] imidazo[1, 2-c]pyrimidin-1(6H)-one and2-(3,5-difluorophenoxy)-5-(hydroxymethyl)benzonitrile.

LC-MS (ESI): m/z 437 [M+H]⁺; 2.96 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.95-7.95 (d, 1H), 7.72-7.69 (dd, 1H),7.59-7.47 (m, 2H), 7.09-7.04 (m, 2H), 5.31 (s, 1H), 5.31-5.23 (q, 2H),4.09-4.00 (m, 2H), 3.89-3.83 (m, 1H), 3.31-3.25 (m, 2H), 2.04-1.81 (m,3H), 1.48-1.38 (m, 1H).

E893-((3,4,5-Trifluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from 3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3,4,5-trifluorophenyl)methanol.

LC-MS (ESI): m/z 338 [M+H]⁺; 2.53 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.40-7.36 (m, 2H), 5.33 (s, 1H), 5.33-5.20(q, 2H), 4.04-4.00 (m, 2H), 3.89-3.85 (m, 1H), 3.31-3.27 (m, 2H),2.01-1.87 (m, 3H), 1.48-1.41 (m, 1H).

E903-((3,5-Difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from 3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 482 [M+H]⁺; 2.85 min (ret time).

¹H NMR (400 MHz, CD₃OD): δ 8.73 (s, 2H), 7.35-7.33 (m, 2H), 5.41 (s,1H), 5.45-5.36 (q, 2H), 4.19-4.15 (m, 2H), 4.03-3.97 (m, 1H), 3.48-3.33(m, 2H), 2.18-1.97 (m, 3H), 1.57-1.47 (m, 1H).

E91(S)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (S)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3-fluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 482 [M+H]⁺; 2.85 min (ret time).

¹H NMR (400 MHz, CD₃OD): δ 8.73 (s, 2H), 7.35-7.33 (m, 2H), 5.41 (s,1H), 5.45-5.36 (q, 2H), 4.19-4.15 (m, 2H), 4.03-3.97 (m, 1H), 3.48-3.33(m, 2H), 2.17-1.97 (m, 3H), 1.57-1.47 (m, 1H).

E923-((4-((3,3-difluorocyclohexyl)oxy)-3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from 3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(4-((3,3-difluorocyclohexyl)oxy)-3,5-difluorophenyl)methanol.

LC-MS (ESI): m/z 454 [M+H]⁺; 3.13 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.23-7.21 (d, 2H), 5.33 (s, 1H), 5.28-5.18(q, 2H), 4.22-3.85 (m, 4H), 3.33-3.27 (m, 3H), 2.19-1.75 (m, 8H),1.59-1.43 (m, 3H).

E93(S)-3-((4-((3,3-difluorocyclohexyl)oxy)-3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from 3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(4-((3,3-difluorocyclohexyl)oxy)-3,5-difluorophenyl)methanol.

LC-MS (ESI): m/z 454 [M+H]⁺; 3.14 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.23-7.21 (d, 2H), 5.33 (s, 1H), 5.28-5.18(q, 2H), 4.22-3.85 (m, 4H), 3.33-3.27 (m, 3H), 2.19-1.75 (m, 8H),1.59-1.43 (m, 3H).

E943-((4-((3,3-difluorocyclopentyl)oxy)-3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from 3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(4-((3,3-difluorocyclopentyl)oxy)-3,5-difluorophenyl)methanol.

LC-MS (ESI): m/z 440 [M+H]⁺; 2.81 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.24-7.24 (d, 2H), 5.33 (s, 1H), 5.26-5.18(q, 2H), 4.85 (s, 1H), 4.10-4.00 (m, 2H), 3.89-3.80 (m, 1H), 3.33-3.27(m, 3H), 2.40-1.87 (m, 8H), 1.46-1.41 (m, 1H).

E95(S)-3-((4-((3,3-difluorocyclopentyl)oxy)-3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (S)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(4-((3,3-difluorocyclohexyl)oxy)-3,5-difluorophenyl)methanol.

LC-MS (ESI): m/z 440 [M+H]⁺; 2.81 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.24-7.24 (d, 2H), 5.33 (s, 1H), 5.26-5.18(q, 2H), 4.85 (s, 1H), 4.10-4.00 (m, 2H), 3.89-3.80 (m, 1H), 3.33-3.27(m, 3H), 2.40-1.87 (m, 8H), 1.46-1.41 (m, 1H).

E963-((3,5-Difluoro-4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from 3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3,5-difluoro-4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 487 [M+H]⁺; 2.11 min (ret time).

¹H NMR (400 MHz, CD₃OD): δ 8.03-8.01 (d, 2H), 6.13 (s, 1H), 6.05-5.98(q, 2H), 5.56-5.54 (m, 1H), 4.85-4.81 (m, 2H), 4.70-4.66 (m, 1H),4.44-4.41 (m, 2H), 4.12-4.08 (m, 2H), 3.94-3.91 (m, 2H), 3.47-3.43 (m,2H), 3.18-3.06 (m, 2H), 2.86-2.68 (m, 3H), 2.28-2.22 (m, 1H).

E97(S)-3-((3,5-difluoro-4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (S)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3,5-difluoro-4-((1-(3,3,3-trifluoropropyl)azetidin-3-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 487 [M+H]⁺; 2.10 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 8.03-8.01 (d, 2H), 6.13 (s, 1H), 6.05-5.98(q, 2H), 5.56-5.54 (m, 1H), 4.85-4.81 (m, 2H), 4.70-4.66 (m, 1H),4.44-4.41 (m, 2H), 4.12-4.08 (m, 2H), 3.94-3.91 (m, 2H), 3.47-3.43 (m,2H), 3.18-3.06 (m, 2H), 2.86-2.68 (m, 3H), 2.28-2.22 (m, 1H).

E983-((4-((1-Butylazetidin-3-yl)oxy)-3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from 3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(4-((1-butylazetidin-3-yl)oxy)-3,5-difluorophenyl)methanol.

LC-MS (ESI): m/z 447 [M+H]⁺; 2.06 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.21-7.18 (d, 2H), 5.32-5.16 (m, 3H), 4.71(s, 1H), 4.04-3.78 (m, 2H), 3.58-3.55 (m, 2H), 3.31-3.27 (m, 1H),3.01-2.98 (m, 2H), 2.83 (s, 1H), 2.41-2.34 (m, 2H), 2.01-1.87 (m, 2H),1.46-1.41 (m, 1H), 1.30-1.20 (m, 6H), 0.87-0.84 (m, 3H).

E993-((3,5-Difluoro-4-(3-fluoropropyl)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from 3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3,5-difluoro-4-(3-fluoropropyl)phenyl)methanol.

LC-MS (ESI): m/z 380 [M+H]⁺; 2.61 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.13-7.11 (d, 2H), 5.34 (s, 1H), 5.26-5.21(m, 2H), 4.54-4.39 (m, 2H), 4.04-4.00 (m, 2H), 3.87-3.85 (m, 1H),3.30-3.28 (m, 2H), 2.74-2.68 (m, 2H), 2.05-1.80 (m, 5H), 1.48-1.38 (m,1H).

E100(R)-3-((2,4-difluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (R)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(2,4-difluoro-phenyl)methanol.

LC-MS (ESI): m/z 320 [M+H]⁺; 3.65 min (ret time).

¹H NMR (400 MHz, CDCl₃): δ 7.46 (q, 1H), 6.89-6.80 (m, 2H), 5.46-5.35(m, 2H), 5.09 (s, 1H), 4.21-4.01 (m, 3H), 3.43-3.36 (m, 1H), 3.29-3.20(m, 1H), 2.19-1.95 (m, 3H), 1.51-1.40 (m, 1H).

E101 (R)-3-((2, 3-difluorobenzyl) oxy)-7, 8, 8a, 9-tetrahydropyrrolo[1′, 2′:3, 4]imidazo[1,2-c] pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (R)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(2,3-difluoro-phenyl)methanol.

LC-MS (ESI): m/z 320[M+H]⁺; 3.65 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.25-7.02 (m, 3H), 5.51-5.41 (m, 2H), 5.10(s, 1H), 4.21-4.02 (m, 3H), 3.44-3.36 (m, 1H), 3.30-3.21 (m, 1H),2.20-1.93 (m, 3H), 1.52-1.38 (m, 1H).

E102(R)-3-((3-fluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (R)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3-fluorophenyl)methanol.

LC-MS (ESI): m/z 302 [M+H]⁺; 3.60 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.35-7.28 (m, 1H), 7.17-7.10 (m, 2H),7.02-6.96 (m, 1H), 5.44-5.33 (m, 2H), 5.12 (s, 1H), 4.21-4.00 (m, 3H),3.45-3.37 (m, 1H), 3.30-3.21 (m, 1H), 2.19-1.93 (m, 3H), 1.52-1.38 (m,1H).

E103(R)-3-((3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (R)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(2,4-difluoro-phenyl)methanol.

1H NMR (300 MHz, CDCl₃): δ 6.91 (d, 2H), 6.77-6.71 (m, 1H), 5.43-4.32(m, 2H), 5.14 (s, 1H), 4.22-4.03 (m, 3H), 3.46-3.39 (m, 1H), 3.32-3.23(m, 1H), 2.20-1.95 (m, 3H), 1.53-1.39 (m, 1H).

LC-MS (ESI): m/z 320 [M+H]⁺; 3.78 min (ret time).

E104(R)-3-((3-fluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

To a solution of(R)-3-chloro-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one(100 mg, 0.473 mmol) and (3-fluorophenyl)methanamine (118 mg, 0.946mmol) in 1,4-dioxane (4 mL) was added diisopropylethylamine (610 mg,4.73 mmol) at room temperature. The reaction mixture was heated to 120°C. under microwave for 2 hours, concentrated under reduced pressure andpurified with prep-HPLC to give the title compound (135 mg, 96%) as apale yellow solid.

LC-MS (ESI): m/z 301 [M+H]⁺; 2.87 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.29-7.22 (m, 1H), 7.09-7.00 (m, 2H),6.94-6.88 (m, 1H), 4.74 (s, 1H), 4.57 (br s, 2H), 4.11-3.91 (m, 3H),3.35-3.28 (m, 1H), 3.19-3.10 (m, 1H), 2.11-1.87 (m, 3H), 1.45-1.34 (m,1H).

E105(R)-3-((3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (R)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)phenyl)methanol.

LC-MS (ESI): m/z 422 [M+H]⁺; 4.37 min (ret time).

¹H NMR (400 MHz, CDCl₃): δ 6.97-6.94 (m, 2H), 5.35-5.26 (m, 2H), 5.11(s, 1H), 4.85-4.82 (m, 1H), 4.74-4.71 (m, 1H), 4.17-4.02 (m, 3H),3.44-3.38 (m, 1H), 3.29-3.25 (m, 1H), 2.18-2.00 (m, 5H), 1.57-1.45 (m,1H), 1.10-1.07 (m, 2H), 0.65 (t, 2H).

E106(R)-3-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo [1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from (R)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 427 [M+H]⁺; 2.01 min (ret time).

¹H NMR (400 MHz, CD₃OD): δ 8.33-8.31 (d, 1H), 7.31-7.29 (d, 2H),6.87-6.81 (m, 2H), 5.44-5.35 (m, 3H), 4.18-4.15 (m, 2H), 4.03-3.97 (m,1H), 3.48-3.37 (m, 2H), 3.12 (s, 3H), 2.18-1.98 (m, 3H), 1.58-1.50 (m,1H).

E107 7-((3, 5-Difluoro-4-((2-(trifluoromethyl) pyridin-4-yl) oxy)benzyl) oxy)-3, 4, 11, 11a-tetra hydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 497 [M+H]⁺; 2.64 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 8.70-8.68 (d, 1H), 7.68 (s, 1H), 7.46-6.44(d, 2H), 7.33-7.31 (m, 1H), 5.42 (s, 1H), 5.34 (s, 2H), 4.11-4.3.79 (m,4H), 3.68-3.33 (m, 5H).

E1087-((3,5-Difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 432 [M+H]⁺; 2.11 min (ret time).

¹H NMR (400 MHz, MeOD-d₄): δ 7.61 (s, 1H), 7.31-7.27 (m, 3H), 5.39 (s,1H), 5.26 (s, 2H), 4.04-3.80 (m, 4H), 3.73 (s, 3H), 3.66-3.33 (m, 5H).

E1097-((4-((1-Ethyl-1H-pyrazol-4-yl)oxy)-3,5-difluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (4-((1-ethyl-1H-pyrazol-4-yl)oxy)-3,5-difluorophenyl)methanol.

LC-MS (ESI): m/z 446 [M+H]⁺; 3.45 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.66 (s, 1H), 7.31-7.27 (m, 3H), 5.39 (s,1H), 5.27 (s, 2H), 4.09-3.79 (m, 6H), 3.66-3.51 (s, 2H), 3.40-3.24 (m,3H), 1.33-1.29 (t, 3H).

E1107-((3,5-Difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)benzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (4-((1-ethyl-1H-pyrazol-4-yl)oxy)-3,5-difluorophenyl)methanol.

LC-MS (ESI): m/z 498 [M+H]⁺; 2.65 min (ret time).

¹H NMR (400 MHz, CD₃OD): δ 8.70 (s, 2H), 7.32-7.30 (d, 2H), 5.38-5.35(m, 3H), 4.14-3.87 (m, 4H), 3.66-3.50 (m, 3H), 3.44-3.33 (t, 2H).

E1112-(4-Fluoro-3-(trifluoromethyl)phenoxy)-5-(((9-oxo-1,3,4,9,11,11a-hexahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-7-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E63 starting from7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand2-(4-fluoro-3-(trifluoromethyl)phenoxy)-5-(hydroxymethyl)benzonitrile.

LC-MS (ESI): m/z 503 [M+H]⁺; 2.85 min (ret time).

¹H NMR (400 MHz, CD₃OD): δ 7.95 (s, 1H), 7.71-7.62 (m, 4H), 7.08-7.05(d, 1H), 5.36 (s, 1H), 5.27 (s, 2H), 3.99-3.80 (m, 4H), 3.65-3.51 (m,2H), 3.44-3.33 (t, 3H).

E112(S)-7-((3,5-difluoro-4-((1-propyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-3,4,11,11atetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(S)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (3,5-difluoro-4-((1-propyl-1H-pyrazol-4-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 460 [M+H]⁺; 2.54 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.65 (s, 1H), 7.31-7.28 (m, 3H), 5.39 (s,1H), 5.26 (s, 2H), 4.09-3.79 (m, 6H), 3.66-3.51 (s, 2H), 3.40-3.24 (m,3H), 1.77-1.68 (m, 2H), 0.80-0.76 (t, 3H).

E113 (S)-7-((3, 5-difluoro-4-((2-(trifluoromethyl) pyridin-4-yl) oxy)benzyl) oxy)-3, 4, 11, 11a tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(S)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 497 [M+H]⁺; 2.66 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 8.70-8.68 (d, 1H), 7.67 (s, 1H), 7.46-7.44(d, 2H), 7.32-7.31 (m, 1H), 5.42 (s, 1H), 5.34 (s, 2H), 4.11-3.79 (m,4H), 3.68-3.26 (m, 5H).

E114(S)-7-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(S)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 432 [M+H]⁺; 2.19 min (ret time).

¹H NMR (400 MHz, CD₃OD): δ 7.61 (s, 1H), 7.31-7.27 (m, 3H), 5.39 (s,1H), 5.26 (s, 2H), 4.04-3.80 (m, 4H), 3.73 (s, 3H), 3.66-3.33 (m, 5H).

E115(S)-7-((4-((1-ethyl-1H-pyrazol-4-yl)oxy)-3,5-difluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido [6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(S)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (4-((1-ethyl-1H-pyrazol-4-yl)oxy)-3,5-difluorophenyl)methanol.

LC-MS (ESI): m/z 446 [M+H]⁺; 2.34 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.66 (s, 1H), 7.31-7.27 (m, 3H), 5.39 (s,1H), 5.27 (s, 2H), 4.04-3.80 (m, 6H), 3.66-3.51 (s, 2H), 3.40-3.24 (m,3H), 1.33-1.29 (t, 3H).

E116(S)-7-((3,4,5-trifluorobenzyl)oxy)-3,4,11,11atetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(S)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (3,4,5-trifluorophenyl)methanol.

LC-MS (ESI): m/z 354 [M+H]⁺; 2.16 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.39-7.35 (m, 2H), 5.38 (s, 1H), 5.24 (s,2H), 4.05-3.80 (m, 4H), 3.66-3.66 (m, 1H), 3.40-3.20 (m, 4H).

E117(R)-7-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-3,4,11,11atetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(R)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 443 [M+H]⁺; 1.74 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 8.36-8.35 (d, 1H), 7.41-7.39 (d, 2H),6.88-6.81 (m, 2H), 5.41 (s, 1H), 5.32 (s, 2H), 4.06-3.81 (m, 4H),3.67-3.53 (m, 2H), 3.44-3.25 (m, 3H), 2.43 (s, 3H).

E118(R)-7-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-3,4,11,11atetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(R)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 443 [M+H]⁺; 1.74 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 8.26-8.26 (d, 1H), 7.39-7.23 (d, 2H),6.88-6.81 (m, 2H), 5.40 (s, 1H), 5.30 (s, 2H), 4.06-3.81 (m, 4H),3.67-3.53 (m, 2H), 3.44-3.25 (m, 3H), 2.44 (s, 3H).

E119 (R)-7-((3, 5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-3, 4, 11, 11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(R)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 497 [M+H]⁺; 2.65 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 8.70-8.68 (d, 1H), 7.67 (s, 1H), 7.46-7.44(d, 2H), 7.32-7.31 (m, 1H), 5.42 (s, 1H), 5.34 (s, 2H), 4.06-3.81 (m,4H), 3.67-3.26 (m, 5H).

E120(R)-7-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(R)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 432 [M+H]⁺; 2.12 min (ret time).

¹H NMR (400 MHz, MeOD-d₄): δ 7.61 (s, 1H), 7.28-7.27 (m, 3H), 5.38 (s,1H), 5.27 (s, 2H), 4.05-3.80 (m, 4H), 3.73 (s, 3H), 3.66-3.27 (m, 5H).

E121(R)-7-((4-((1-ethyl-1H-pyrazol-4-yl)oxy)-3,5-difluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido [6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(R)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (4-((1-ethyl-1H-pyrazol-4-yl)oxy)-3,5-difluorophenyl)methanol.

LC-MS (ESI): m/z 446 [M+H]⁺; 2.36 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.66 (s, 1H), 7.31-7.28 (m, 3H), 5.38 (s,1H), 5.27 (s, 2H), 4.04-3.80 (m, 6H), 3.66-3.51 (s, 2H), 3.40-3.24 (m,3H), 1.33-1.29 (t, 3H).

E122(R)-7-((3,5-difluoro-4-((1-propyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-3,4,11,11atetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(R)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (3,5-difluoro-4-((1-propyl-1H-pyrazol-4-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 460 [M+H]⁺; 2.55 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.65 (s, 1H), 7.31-7.28 (m, 3H), 5.39 (s,1H), 5.26 (s, 2H), 4.09-3.79 (m, 6H), 3.66-3.51 (s, 2H), 3.40-3.24 (m,3H), 1.77-1.68 (m, 2H), 0.80-0.76 (t, 3H).

E123(R)-7-((3,4,5-trifluorobenzyl)oxy)-3,4,11,11atetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(R)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (3,4,5-trifluorophenyl)methanol.

LC-MS (ESI): m/z 354 [M+H]⁺; 2.17 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.39-7.35 (m, 2H), 5.38 (s, 1H), 5.24 (s,2H), 4.05-3.80 (m, 4H), 3.66-3.66 (m, 1H), 3.40-3.20 (m, 4H).

E124(S)-7-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-3,4,11,11atetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(S)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 443 [M+H]⁺; 1.76 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 8.36-8.35 (d, 1H), 7.41-7.39 (d, 2H),6.88-6.81 (m, 2H), 5.41 (s, 1H), 5.32 (s, 2H), 4.06-3.81 (m, 4H),3.67-3.53 (m, 2H), 3.44-3.25 (m, 3H), 2.43 (s, 3H).

E125(S)-7-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-3,4,11,11atetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(S)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)phenyl)methanol.

LC-MS (ESI): m/z 443 [M+H]⁺; 1.82 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 8.26-8.26 (d, 1H), 7.39-7.23 (d, 2H),6.88-6.81 (m, 2H), 5.40 (s, 1H), 5.30 (s, 2H), 4.06-3.81 (m, 4H),3.67-3.53 (m, 2H), 3.44-3.25 (m, 3H), 2.44 (s, 3H).

E126(S)-7-((2,4-difluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(S)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (2,4-difluorophenyl)methanol.

LC-MS (ESI): m/z 336 [M+H]⁺; 3.29 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.45 (q, 1H), 6.89-6.79 (m, 2H), 5.40 (t,2H), 4.99 (s, 1H), 4.18-3.88 (m, 4H), 3.70-3.63 (m, 1H), 3.56-3.30 (m,4H).

E127(S)-7-((2,3-difluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(S)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (2,3-difluorophenyl)methanol.

LC-MS (ESI): m/z 336 [M+H]⁺; 3.29 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.24-7.02 (m, 3H), 5.47 (t, 2H), 5.01 (s,1H), 4.19-3.88 (m, 4H), 3.70-3.64 (m, 1H), 3.57-3.34 (m, 4H).

E128(S)-7-((3-fluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(S)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (3-fluorophenyl) methanol.

LC-MS (ESI): m/z 318 [M+H]⁺; 3.26 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.35-7.28 (m, 1H), 7.17-7.10 (m, 2H),7.03-6.96 (m, 1H), 5.43-5.34 (m, 2H), 5.03 (s, 1H), 4.19-3.90 (m, 4H),3.70-3.64 (m, 1H), 3.58-3.35 (m, 4H).

E129(S)-7-((3,5-difluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(S)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (3, 5-difluorophenyl)methanol.

LC-MS (ESI): m/z 336[M+H]⁺; 3.38 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 6.91 (d, 2H), 6.76-6.69 (m, 1H), 5.42-5.33(m, 2H), 5.04 (s, 1H), 4.19-3.91 (m, 4H), 3.70-3.64 (m, 1H), 3.57-3.35(m, 4H).

E130(R)-7-((2,4-difluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(R)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (2,4-difluorophenyl)methanol.

LC-MS (ESI): m/z 336 [M+H]⁺; 3.16 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.50-7.42 (m, 1H), 6.90-6.79 (m, 2H), 5.41(s, 2H), 4.99 (s, 1H), 4.19-3.89 (m, 4H), 3.70-3.65 (m, 1H), 3.57-3.31(m, 4H).

E131(R)-7-((2,3-difluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(R)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (2,3-difluorophenyl)methanol.

LC-MS (ESI): m/z 336 [M+H]⁺; 3.32 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.25-7.03 (m, 3H), 5.47 (t, 2H), 5.01 (s,1H), 4.19-3.89 (m, 4H), 3.70-3.64 (m, 1H), 3.58-3.32 (m, 4H).

E132(R)-7-((3-fluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(R)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (3-fluorophenyl) methanol.

LC-MS (ESI): m/z 318 [M+H]⁺; 3.26 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.36-7.27 (m, 1H), 7.18-7.10 (m, 2H),7.04-6.97 (m, 1H), 5.44-5.35 (m, 2H), 5.04 (s, 1H), 4.19-3.91 (m, 4H),3.70-3.65 (m, 1H), 3.58-3.35 (m, 4H).

E133(R)-7-((3,5-difluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(R)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (3, 5-difluorophenyl) methanol.

LC-MS (ESI): m/z 336[M+H]⁺; 3.39 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 6.94-6.88 (m, 2H), 6.78-6.70 (m, 1H),5.43-5.33 (m, 2H), 5.04 (s, 1H), 4.20-3.92 (m, 4H), 3.70-3.65 (m, 1H),3.59-3.36 (m, 4H).

E134(S)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one

To a solution of(S)-3-chloro-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one(60 mg, 0.26 mmol) and(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol(88 mg, 0.29 mmol) in DMF (4 mL) was added NaH (60% in mineral oil, 21mg, 0.52 mmol) at 0° C. The reaction was stirred at room temperature for2 hours. The mixture was then quenched with ice-water and extracted withEtOAc (40 mL×3). The extracts were combined and dried over Na₂SO₄,filtered, concentrated under reduced pressure. The crude was thenpurified with prep-HPLC (Column: XB C18, 4.6×33 mm; Mobile phase: A:H₂O, B: MeCN, 30-95% B) to give the title compound (40 mg, yield 31%) asa white solid.

LC-MS (ESI): m/z 497 [M+H]⁺; 3.52 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 8.62 (d, J=5.7 Hz, 1H), 7.28 (s, 1H),7.16-7.13 (m, 2H), 7.01-6.99 (m, 1H), 5.51-5.40 (m, 2H), 5.29 (d, J=3.3Hz, 1H), 5.07 (d, J=11.7 Hz, 1H), 4.67 (d, J=11.1 Hz, 1H), 4.19-4.06 (m,3H), 4.00-3.96 (m, 1H), 3.84-3.80 (m, 1H), 2.00-1.97 (m, 1H), 1.72-1.67(m, 1H).

E135(R)-3-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(R)-3-chloro-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one(60 mg, 0.26 mmol) and(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol(88 mg, 0.29 mmol) as a white solid.

LC-MS (ESI): m/z 497 [M+H]⁺; 3.52 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 8.60 (d, J=5.7 Hz, 1H), 7.28 (s, 1H),7.14-7.11 (m, 2H), 6.99-6.96 (m, 1H), 5.48-5.37 (m, 2H), 5.27 (s, 1H),5.05 (d, J=11.7 Hz, 1H), 4.65 (d, J=11.1 Hz, 1H), 4.19-4.06 (m, 3H),4.00-3.96 (m, 1H), 3.84-3.80 (m, 1H), 2.00-1.97 (m, 1H), 1.70-1.64 (m,1H).

E136(S)-3-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-8,9,9a,10-tetrahydropyri-mdo[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)methanol (70 mg,0.29 mmol) and(S)-3-chloro-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-on(60 mg, 0.26 mmol) as a white solid.

LC-MS (ESI): m/z 432 [M+H]⁺; 3.29 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.29-7.24 (m, 1H), 7.18 (s, 1H), 7.02-6.99(m, 2H), 5.41-5.30 (m. 2H), 5.24 (m. 1H), 5.03 (d, J=11.4 Hz, 1H), 4.64(d, J=11.1 Hz, 1H), 4.16-4.15 (m, 2H), 4.15-4.12 (m, 1H), 4.10-4.03 (m,1H), 3.93-3.77 (m, 3H), 3.77-3.73 (m, 1H), 2.00-1.95 (m, 1H), 1.68-1.58(m, 1H).

E137(R)-3-((3,5-difluoro-4-((1-methyl-H-pyrazol-4-yl)oxy)benzyl)oxy)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl) methanol (70 mg,0.29 mmol) and(R)-3-chloro-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one(60 mg, 0.26 mmol) as a white solid.

LC-MS (ESI): m/z 432 [M+H]⁺; 3.30 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.27-7.26 (m, 1H), 7.18 (s, 1H), 7.04-6.99(m, 2H), 5.41-5.30 (m, 2H), 5.24 (s. 1H), 5.03 (d, J=11.4 Hz, 1H), 4.63(d, J=11.1 Hz, 1H), 4.18-4.15 (m, 2H), 4.12-4.10 (m, 1H), 4.10-4.03 (m,1H), 3.97-3.93 (m, 3H), 3.81-3.73 (m, 1H), 2.00-1.95 (m, 1H), 1.68-1.58(m, 1H).

E138(S)-3-((3-fluorobenzyl)oxy)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(S)-3-chloro-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one(50 mg, 0.20 mmol) and (3-fluorophenyl)methanol (28 mg, 0.22 mmol) as awhite solid.

LC-MS (ESI): m/z 318 [M+H]⁺; 3.40 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.35-7.24 (m, 1H), 7.17-7.10 (m, 2H),7.03-6.96 (m, 1H), 5.44-5.35 (m, 1H), 5.24 (s, 1H), 5.02 (d, J=11.7 Hz,1H), 4.62 (t, J=6.9 Hz, 1H), 4.18-4.02 (m, 3H), 3.99-3.93 (m, 1H),3.80-3.72 (m, 1H), 2.04-1.93 (m, 1H), 1.69-1.56 (m, 1H).

E139(S)-3-((3,4,5-trifluorobenzyl)oxy)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(S)-3-chloro-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one(50 mg, 0.20 mmol) and (3,4,5-trifluorophenyl)methanol (36 mg, 0.22mmol) as a white solid.

LC-MS (ESI): m/z 354 [M+H]⁺; 3.69 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.05-7.00 (m, 2H), 5.38-5.28 (m, 2H), 5.24(s, 1H), 5.03 (d, J=11.1 Hz, 1H), 4.63 (d, J=11.1 Hz, 1H), 4.16-4.02 (m,3H), 3.99-3.92 (m, 1H), 3.82-3.73 (m, 1H), 1.99-1.63 (m, 1H), 1.57-1.54(m, 1H).

E140(S)-3-((3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)benzyl)oxy)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)phenyl)methanol (40 mg,0.16 mmol) and(S)-3-chloro-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one(35 mg, 0.16 mmol) as yellow oil.

LC-MS (ESI): m/z 438 [M+H]⁺; 4.07 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 6.97-6.92 (m, 2H), 5.35-5.25 (m, 2H), 5.22(s, 1H), 5.02 (d, J=12.3 Hz, 1H), 4.84 (t, J=6.3 Hz, 1H), 4.71-4.60 (m,2H), 4.16-4.01 (m, 3H), 3.95-3.90 (m, 1H), 3.80-3.71 (m, 1H), 2.18-2.07(m, 2H), 1.97-1.91 (m, 1H), 1.67-1.62 (m, 1H), 1.09-1.05 (m, 2H),0.66-0.62 (m, 2H).

E141(S)-6-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from((S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol(63 mg, 0.21 mmol) as a white solid.

LC-MS (ESI): m/z 483 [M+H]⁺; 4.04 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 8.60 (d, J=5.7 Hz, 1H), 7.26 (s, 1H), 7.15(d, J=7.8 Hz, 2H), 5.43 (d, J=3.6 Hz, 2H), 5.39 (s, 1H), 4.99 (d, J=6.0Hz, 1H), 4.60 (d, J=6.0 Hz, 1H), 4.29-4.11 (m, 4H), 3.55-3.50 (m, 1H).

E142(R)-6-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(R)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol(58 mg, 0.19 mmol) as a red solid.

LC-MS (ESI): m/z 483 [M+H]⁺; 3.54 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 8.60 (d, J=5.4 Hz, 1H), 7.26 (d, J=2.7 Hz,1H), 7.13 (d, J=8.1 Hz, 2H), 6.99-6.97 (m, 1H), 5.48-5.37 (m, 3H), 5.10(d, J=5.7 Hz, 1H), 4.60 (d, J=6.0 Hz, 1H), 4.32-4.09 (m, 4H), 3.55-3.50(m, 1H).

E143(S)-6-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and(3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)methanol (49 mg,0.21 mmol) as a white solid.

LC-MS (ESI): m/z 418 [M+H]⁺; 3.36 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.27 (d, J=2.1 Hz, 1H), 7.19 (s, 1H), 7.02(d, J=6.3 Hz, 2H), 5.40-5.32 (m, 3H), 4.99 (d, J=4.5 Hz, 1H), 4.59 (d,J=4.2 Hz, 1H), 4.29-4.09 (m, 4H), 3.82 (s, 1H), 3.53-3.50 (m, 1H).

E144(R)-6-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(R)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and(3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)methanol (47 mg,0.19 mmol) as a yellow solid.

LC-MS (ESI): m/z 418 [M+H]⁺; 3.36 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.25 (d, J=2.1 Hz, 1H), 7.01 (s, 1H), 6.99(d, J=8.4 Hz, 2H), 5.34 (d, J=3.6 Hz, 3H), 4.96 (d, J=6.0 Hz, 1H), 4.57(d, J=6.0 Hz, 1H), 4.26-4.06 (m, 4H), 3.79 (s, 3H), 3.52-3.47 (m, 1H).

E145(S)-6-((4-chloro-3-fluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(35 mg, 0.16 mmol) and (4-chloro-3-fluorophenyl)methanol (29 mg, 0.18mmol) as a white solid.

LC-MS (ESI): m/z 338 [M+H]⁺; 3.64 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.40-7.26 (m, 1H), 7.27-7.19 (m, 1H),7.13-7.11 (m, 1H), 5.37-5.36 (m, 2H), 5.36-5.34 (m, 2H), 4.97 (d, J=5.7Hz, 1H), 4.58 (d, J=6.0 Hz, 1H), 4.27-4.17 (m, 3H), 4.14-4.10 (m, 1H),3.53-3.48 (m, 1H).

E146(S)-6-((3,4,5-trifluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(35 mg, 0.16 mmol) and (3,4,5-trifluorophenyl)methanol (29 mg, 0.18mmol) as a white solid.

LC-MS (ESI): m/z 340 [M+H]⁺; 3.57 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.05-7.00 (m, 2H), 5.33 (d, J=5.7 Hz, 3H),5.31 (s, 2H), 4.97 (d, J=6.0 Hz, 1H), 4.59 (d, J=5.7 Hz, 1H), 4.27-4.13(m, 3H), 4.10-4.08 (m, 1H), 3.54-3.48 (m, 1H).

E147(S)-6-((3,5-difluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(35 mg, 0.16 mmol) and (3,5-difluorophenyl)methanol (26 mg, 0.18 mmol)as a white solid.

LC-MS (ESI): m/z 322 [M+H]⁺; 3.43 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 6.93-6.91 (m, 2H), 6.78-6.72 (m, 1H), 5.37(t, J=4.2 Hz, 3H), 4.98 (d, J=6.0 Hz, 1H), 4.59 (d, J=5.7 Hz, 1H),4.30-4.08 (m, 4H), 3.54-3.48 (m, 1H).

E148(S)-6-((3-fluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(35 mg, 0.16 mmol) and (3-fluorophenyl)methanol (23 mg, 0.18 mmol) as awhite solid.

LC-MS (ESI): m/z 304 [M+H]⁺; 3.30 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.33-7.29 (m, 1H), 7.18-7.10 (m, 2H),7.04-7.00 (m, 1H), 5.39 (d, J=3.0 Hz, 2H), 5.35 (s, 1H), 4.97 (d, J=5.7Hz, 1H), 4.59 (d, J=5.7 Hz, 1H), 4.29-4.07 (m, 4H), 3.53-3.48 (m, 1H).

E149(S)-6-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from((S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and(3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)phenyl)methanol (52 mg, 0.21mmol) as a white solid.

LC-MS (ESI): m/z 429 [M+H]⁺; 3.55 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 8.28 (t, J=1.8 Hz, 1H), 7.10-7.05 (m, 4H),5.38 (t, J=4.5 Hz, 3H), 4.98 (d, J=5.7 Hz, 1H), 4.60 (d, J=6.0 Hz, 1H),4.29-4.11 (m, 4H), 3.55-3.49 (m, 1H), 2.52 (s, 3H).

E150(S)-6-((3,5-difluoro-4-((1-propyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and(3,5-difluoro-4-((1-propyl-1H-pyrazol-4-yl)oxy)phenyl)methanol (55 mg,0.21 mmol) as a white solid.

LC-MS (ESI): m/z 446 [M+H]⁺; 3.78 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.27-7.23 (m, 1H), 7.20-7.19 (m, 1H),7.03-6.99 (m, 2H), 5.35 (s, 3H), 4.98 (t, J=4.2 Hz, 1H), 4.59 (t, J=4.2Hz, 1H), 4.28-4.10 (m, 4H), 3.96 (t, J=7.8 Hz, 2H), 3.54-3.48 (m, 1H),1.87-1.80 (m, 2H), 0.92-0.86 (m, 3H).

E151(S)-6-((3,5-difluoro-4-((1-(trifluoromethyl)-1H-pyrazol-4-yl)oxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and(3,5-difluoro-4-((1-(trifluoromethyl)-1H-pyrazol-4-yl)oxy)phenyl)methanol(61 mg, 0.21 mmol) as a white solid.

LC-MS (ESI): m/z 472 [M+H]⁺; 4.11 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.63 (s, 1H), 7.51 (s, 1H), 7.07 (d, J=5.7Hz, 2H), 5.38 (t, J=3.0 Hz, 3H), 4.99 (d, J=4.2 Hz, 1H), 4.60 (d, J=4.5Hz, 1H), 4.29-4.10 (m, 4H), 3.54-3.50 (m, 1H).

E152(S)-6-((3,5-difluoro-4-((2-methylpyrimidin-5-yl)oxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and(3,5-difluoro-4-((2-methylpyrimidin-5-yl)oxy)phenyl)methanol (52 mg,0.21 mmol) as a white solid.

LC-MS (ESI): m/z 430 [M+H]⁺; 3.35 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 8.37 (s, 2H), 7.12 (d, J=8.1 Hz, 2H), 5.41(t, J=3.6 Hz, 3H), 5.01 (d, J=6.0 Hz, 1H), 4.62 (t, J=6.0 Hz, 1H),4.30-4.11 (m, 4H), 3.56-3.51 (m, 1H), 2.73 (s, 3H).

E153(R)-6-((3,4,5-trifluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(R)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and (3,4,5-trifluorophenyl)methanol (27 mg, 0.19mmol) as a white solid.

LC-MS (ESI): m/z 340 [M+H]⁺; 3.58 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.03 (t, J=6.6 Hz, 2H), 5.35-5.28 (m, 3H),4.98 (d, J=5.7 Hz, 1H), 4.59 (d, J=6.0 Hz, 1H), 4.31-4.08 (m, 4H), 3.51(t, J=7.2 Hz, 1H).

E154(R)-6-((3,5-difluoro-4-((1-(trifluoromethyl)-1H-pyrazol-4-yl)oxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(R)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and(3,5-difluoro-4-((1-(trifluoromethyl)-1H-pyrazol-4-yl)oxy)phenyl)methanol(56 mg, 0.19 mmol) as a yellow solid.

LC-MS (ESI): m/z 472 [M+H]⁺; 4.07 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.60 (s, 1H), 7.49 (s, 1H), 7.04 (d, J=8.7Hz, 2H), 5.35 (d, J=5.1 Hz, 3H), 4.96 (d, J=6.0 Hz, 1H), 4.57 (d, J=6.0Hz, 1H), 4.26-4.08 (m, 4H), 3.50-3.49 (m, 1H).

E155(R)-6-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(R)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and(3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)phenyl)methanol (48 mg, 0.19mmol) as a white solid.

LC-MS (ESI): m/z 429 [M+H]⁺; 2.93 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 8.38 (d, J=5.4 Hz, 1H), 7.10 (d, J=8.1 Hz,2H), 6.68 (d, J=8.1 Hz, 2H), 5.42 (t, J=6.9 Hz, 3H), 5.01 (d, J=6.0 Hz,1H), 4.61 (d, J=6.0 Hz, 1H), 4.30-4.13 (m, 4H), 3.55-3.51 (m, 1H), 2.53(m, 3H).

E156(R)-6-((3,5-difluoro-4-((1-propyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(R)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and(3,5-difluoro-4-((1-propyl-1H-pyrazol-4-yl)oxy)phenyl)methanol (51 mg,0.19 mmol) as colorless oil.

LC-MS (ESI): m/z 446 [M+H]⁺; 3.78 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.27 (s, 1H), 7.21 (s, 1H), 7.02 (d, J=8.4Hz, 2H), 5.36 (t, J=1.2 Hz, 2H), 4.98 (d, J=5.7 Hz, 1H), 4.59 (d, J=6.0Hz, 1H), 4.29-4.08 (m, 4H), 3.97 (t, J=6.9 Hz, 2H), 3.54-3.49 (m, 1H),1.87-1.80 (m, 2H), 0.92-0.87 (m, 3H).

E157(R)-6-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(R)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and(3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)phenyl)methanol (48 mg, 0.19mmol) as a yellow oil.

LC-MS (ESI): m/z 429 [M+H]⁺; 3.62 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 8.26 (d, J=2.7 Hz, 1H), 7.10-7.04 (m, 4H)5.37 (t, J=3.6 Hz, 3H), 4.98 (d, J=8.1 Hz, 1H), 5.42 (d, J=5.7 Hz, 1H),4.27-4.17 (m, 4H), 3.54-3.49 (m, 1H), 2.50 (s, 3H).

E158(R)-6-((4-((1-ethyl-1H-pyrazol-4-yl)oxy)-3,5-difluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(R)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and(4-((1-ethyl-1H-pyrazol-4-yl)oxy)-3,5-difluorophenyl)methanol (48 mg,0.19 mmol) as a colorless oil.

LC-MS (ESI): m/z 432 [M+H]⁺; 3.03 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.26 (s, 1H), 7.21 (s, 1H), 7.03-6.99 (m,2H), 5.38 (m, 3H), 4.97 (d, J=3.9 Hz, 1H), 4.58 (d, J=4.5 Hz, 1H), 4.29(m, 7H), 3.52-3.48 (m, 1H), 1.43 (d, J=5.4 Hz, 3H).

E159 (R)-6-((3,5-difluoro-4-((2-methylpyrimidin-5-yl)oxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(R)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and(3,5-difluoro-4-((2-methylpyrimidin-5-yl)oxy)phenyl)methanol (48 mg,0.19 mmol) as a red solid.

LC-MS (ESI): m/z 430 [M+H]⁺; 2.80 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 8.34 (s, 2H), 7.09 (d, J=6.0 Hz, 2H),5.43-5.35 (m, 3H), 4.98 (d, J=4.2 Hz, 1H), 4.59 (d, J=4.5 Hz, 1H),4.30-4.08 (m, 4H), 3.55-3.49 (m, 1H), 2.69 (s, 3H).

E160(S)-6-((4-((1-ethyl-1H-pyrazol-4-yl)oxy)-3,5-difluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and(4-((1-ethyl-1H-pyrazol-4-yl)oxy)-3,5-difluorophenyl)methanol (52 mg,0.21 mmol) as a white solid.

LC-MS (ESI): m/z 432 [M+H]⁺; 3.56 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.28 (s, 1H), 7.22 (s, 1H), 7.02 (d, J=3.3Hz, 2H), 5.36 (t, J=3.0 Hz, 3H), 4.98 (d, J=4.5 Hz, 1H), 4.60 (d, J=1.2Hz, 1H), 4.28-4.16 (m, 4H), 4.13-4.04 (m, 2H), 3.51 (t, J=6.0 Hz, 1H),1.45 (t, J=5.4 Hz, 3H).

E161(S)-6-((3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and(3,5-difluoro-4-((2-methylpyridin-4-yl)oxy)phenyl)methanol (52 mg, 0.21mmol) as a white solid.

LC-MS (ESI): m/z 429 [M+H]⁺; 3.51 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 8.36 (t, J=6.0 Hz, 1H), 7.09 (d, J=5.1 Hz,2H), 6.69-6.65 (m, 2H), 5.41 (d, J=3.0 Hz, 2H), 5.38 (s, 1H), 4.99 (d,J=6.3 Hz, 1H), 4.59 (t, J=5.1 Hz, 1H), 4.29-4.11 (m, 4H), 3.55-3.50 (m,2H), 2.50 (d, J=3.0 Hz, 3H).

E162 and E163 E162: Enantiomer 1:7-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-b][1,3]oxazin-9(2H)-one E:163: Enantiomer 2:7-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-b][1,3]oxazin-9(2H)-one

A mixture of3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-b][1,3]oxazine-7,9(2H,8H)-dione(104 mg, 0.5 mmol) and Ag₂CO₃ (344 mg, 1.3 mmol) in toluene (5 mL) washeated to 70° C. Then,4-(4-(bromomethyl)-2,6-difluorophenoxy)-2-(trifluoromethyl)pyridine (220mg, 0.6 mmol) was added and the mixture was stirred at 110° C. forovernight. The mixture was cooled to room temperature, filtered. Thefiltrate was concentrated. The crude was purified by prep-TLC(DCM/MeOH=30/1) to give a white solid, which was further purified bychiral HPLC to give the title compounds enantiomer 1 (15 mg, yield 6%)and enantiomer 2 (12 mg, yield 5%) as white solids.

Enantiomer 1

LC-MS (ESI): m/z 497 [M+H]⁺; 4.30 min (ret time).

¹H NMR (300 MHz, CD₃OD): δ 8.51 (d, J=6.0 Hz, 1H), 7.33 (d, J=2.4 Hz,1H), 7.24 (d, J=8.7 Hz, 2H), 7.08-7.05 (m, 1H), 5.45 (s, 1H), 5.31 (s,2H), 5.28-5.26 (m, 1H), 4.00-3.84 (m, 2H), 3.84-3.74 (m, 3H), 3.53-3.22(m, 1H), 1.86-1.82 (m, 1H), 1.47-1.44 (m, 1H).

Enantiomer 2

LC-MS (ESI): m/z 497 [M+H]⁺; 3.71 min (ret time).

¹H NMR (300 MHz, CD₃OD): δ 8.51 (d, J=5.7 Hz, 1H), 7.34 (d, J=2.4 Hz,1H), 7.26 (d, J=5.1 Hz, 2H), 7.08-7.06 (m, 1H), 5.46 (s, 1H), 5.31 (s,2H), 5.28-5.26 (m, 1H), 4.00-3.93 (m, 2H), 3.85-3.74 (m, 3H), 3.54-3.44(m, 1H), 1.86-1.80 (m, 1H), 1.48-1.43 (m, 1H).

E164 and E165 E164: Enantiomer 1:6-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-10,10a-dihydro-2H-oxazolo[3′,2′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-oneE165: Enantiomer 2:6-((3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-10,10a-dihydro-2H-oxazolo[3′,2′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

A mixture of10,10a-dihydro-2H-oxazolo[3′,2′:3,4]imidazo[1,2-c]pyrimidine-6,8(3H,7H)-dione(80 mg, 0.410 mmol) and Ag₂CO₃ (282 mg, 1.03 mmol) in toluene (4 mL) washeated to 70° C. Then,4-(4-(bromomethyl)-2,6-difluorophenoxy)-2-(trifluoromethyl)pyridine (166mg, 0.451 mmol) was added and the reaction was then stirred at 100° C.for 2 days. The mixture was cooled to room temperature, filtered. Thefiltrate was concentrated. The residue was purified by prep-TLC(DCM/MeOH=25/1) to give a white solid, which was further purified bychiral HPLC to give the title compounds enantiomer 1 (6 mg, yield 3%)and enantiomer 2 (5 mg, yield 3%) as white solids.

Enantiomer 1

LC-MS (ESI): m/z 483 [M+H]⁺; 3.65 min (ret time).

¹H NMR (300 MHz, CD₃OD): δ 8.51 (d, J=5.7 Hz, 1H), 7.33 (d, J=2.1 Hz,1H), 7.22 (d, J=2.7 Hz, 2H), 7.08-7.05 (m, 1H), 5.58 (s, 1H), 5.32 (s,2H), 5.16-5.14 (m, 1H), 4.07 (s, 2H), 4.06-3.78 (m, 2H), 3.61-3.49 (m,2H).

Enantiomer 2

LC-MS (ESI): m/z 483 [M+H]⁺; 3.65 min (ret time).

¹H NMR (300 MHz, CD₃OD): δ 8.51 (d, J=5.7 Hz, 1H), 7.33 (d, J=2.1 Hz,1H), 7.22 (d, J=2.7 Hz, 2H), 7.08-7.05 (m, 1H), 5.58 (s, 1H), 5.32 (s,2H), 5.16-5.14 (m, 1H), 4.07 (s, 2H), 4.06-3.78 (m, 2H), 3.61-3.49 (m,2H).

E1667-((3,5-Difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-2-methyl-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from7-chloro-2-methyl-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one(50 mg, 0.21 mmol) and(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol(70 mg, 0.23 mmol) as an off-white solid.

LC-MS (ESI): m/z 510 [M+H]⁺; 3.05 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 8.60 (d, J=5.7 Hz, 1H), 7.25-7.23 (m, 1H),7.14-7.11 (m, 2H), 7.00-6.97 (m, 1H), 5.47-5.05 (m, 2H), 5.05 (s, 1H),4.21-4.13 (m, 1H), 4.09-4.00 (m, 1H), 3.77-3.71 (m, 1H), 3.51-3.43 (m,1H), 3.38-3.28 (m, 1H), 2.95-2.91 (m, 1H), 2.82-2.78 (m, 1H), 2.35 (s,3H), 2.17-1.98 (m, 2H).

E1677-((3,5-Difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-2-methyl-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-2H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from7-chloro-2-methyl-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one(50 mg, 0.21 mmol) and(3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)methanol (55 mg,0.23 mmol) as a yellow solid.

LC-MS (ESI): m/z 445 [M+H]⁺; 2.73 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.25-7.18 (m, 1H), 7.17-7.05 (m, 1H),7.04-6.97 (m, 2H), 5.39-5.30 (m, 2H), 5.01 (s, 1H), 4.20-4.12 (m, 1H),4.08-4.00 (m, 1H), 3.81 (s, 3H), 3.79-3.71 (m, 1H), 3.48-3.43 (m, 1H),3.36-3.26 (m, 1H), 2.94-2.89 (m, 1H), 2.81-2.77 (m, 1H), 2.34 (s, 3H),2.17-1.97 (m, 2H).

E168(S)-6-((2,4-difluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from (2,4-difluorophenyl)methanol (26 mg, 0.18 mmol)and(S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(35 mg, 0.16 mmol) as a white solid.

LC-MS (ESI): m/z 322 [M+H]⁺; 3.35 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.46 (d, J=6.6 Hz, 1H), 6.88-6.84 (m, 2H),5.41 (d, J=3.9 Hz, 2H), 5.31 (s, 1H), 4.95 (d, J=5.7 Hz, 1H), 4.57 (d,J=5.7 Hz, 1H), 4.26-4.15 (m, 3H), 4.12-4.07 (m, 1H), 3.52-3.47 (m, 1H).

E169(S)-6-((2,3-difluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from (2,3-difluorophenyl)methanol (26 mg, 0.18 mmol)and(S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(35 mg, 0.16 mmol) as a white solid.

LC-MS (ESI): m/z 322 [M+H]⁺; 3.36 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.26-7.09 (m, 3H), 5.48-5.47 (m, 2H), 5.33(s, 1H), 4.96 (d, J=5.7 Hz, 1H) 4.57 (d, J=5.7 Hz, 1H), 4.27-4.18 (m,3H), 4.14-4.07 (m, 1H), 3.52-3.47 (m, 1H).

E170(R)-6-((4-chloro-3-fluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(R)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and (4-chloro-3-fluorophenyl)methanol (30 mg, 0.19mmol) as a yellow solid.

LC-MS (ESI): m/z 338 [M+H]⁺; 3.64 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.36 (t, J=8.1 Hz, 1H), 7.21-7.09 (m, 2H),5.34 (t, J=6.3 Hz, 3H), 4.96 (d, J=6.0 Hz, 1H), 4.57 (d, J=6.3 Hz, 1H),4.26-4.06 (m, 4H), 3.52-3.46 (m, 1H).

E171(R)-6-((3-fluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(R)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and (3-fluorophenyl)methanol (24 mg, 0.19 mmol) as ayellow solid.

LC-MS (ESI): m/z 304 [M+H]⁺; 3.29 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.33-7.26 (m, 2H), 7.15-7.07 (m, 2H),7.01-6.95 (m, 1H), 5.41-5.33 (m, 3H), 4.95 (d, J=6.0 Hz, 1H), 4.55 (d,J=5.7 Hz, 1H), 4.27-4.04 (m, 4H), 3.50-3.45 (m, 1H).

E172(R)-6-((2,3-difluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(R)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and (2,3-difluorophenyl)methanol (27 mg, 0.19 mmol)as white oil.

LC-MS (ESI): m/z 322 [M+H]⁺; 3.44 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.19-7.06 (m, 3H), 5.45 (t, J=1.8 Hz, 2H),5.31 (s, 1H), 4.94 (d, J=6.3 Hz, 1H), 4.55 (d, J=6.0 Hz, 1H), 4.29-4.05(m, 4H), 3.51-3.46 (m, 1H).

E173(S)-6-((2,4,5-trifluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(35 mg, 0.16 mmol) and (2,4,5-trifluorophenyl)methanol (29 mg, 0.18mmol) as a white solid.

LC-MS (ESI): m/z 340 [M+H]⁺; 3.48 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.32-7.24 (m, 1H), 6.99-6.90 (m, 1H), 5.41(s, 2H), 5.33 (s, 1H), 4.97 (d, J=6.0 Hz, 1H), 4.59 (d, J=6.0 Hz, 1H),4.27-4.08 (m, 4H), 3.53-3.48 (m, 1H).

E174(R)-6-((2,4-difluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(R)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and (2,4-difluorophenyl)methanol (27 mg, 0.19 mmol)as a white solid.

LC-MS (ESI): m/z 322 [M+H]⁺; 3.37 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.45-7.43 (m, 1H), 6.85-6.79 (m, 2H), 5.40(d, J=2.7 Hz, 2H), 5.30 (s, 1H), 4.94 (d, J=5.7 Hz, 1H), 4.56 (d, J=6.0Hz, 1H), 4.26-4.06 (m, 4H), 3.51-3.46 (m, 1H).

E175(R)-6-((2,4,5-trifluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(R)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and (2,4,5-trifluorophenyl)methanol (31 mg, 0.19mmol) as a white solid.

LC-MS (ESI): m/z 340 [M+H]⁺; 3.46 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.34-7.28 (m, 1H), 6.98-6.89 (m, 1H), 5.39(d, J=1.5 Hz, 2H), 5.32 (s, 1H), 4.96 (d, J=4.8 Hz, 1H), 4.57 (d, J=6.0Hz, 1H), 4.29-4.07 (m, 4H), 3.53-3.47 (m, 1H).

E176(R)-6-((3,5-difluorobenzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(R)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.19 mmol) and (3,5-difluorophenyl)methanol (27 mg, 0.19 mmol)as yellow oil.

LC-MS (ESI): m/z 322 [M+H]⁺; 3.43 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 6.90 (d, J=6.0 Hz, 2H), 6.77-6.70 (m, 1H),5.41-5.32 (m, 3H), 4.97 (d, J=5.4 Hz, 12H), 4.58 (d, J=6.0 Hz, 1H),4.31-4.07 (m, 4H), 3.52-3.47 (m, 1H).

E177(R)-3-((2,4-difluorobenzyl)oxy)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(R)-3-chloro-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one(45 mg, 0.20 mmol) and (2,4-difluorophenyl)methanol (32 mg, 0.22 mmol)as a white solid.

LC-MS (ESI): m/z 336 [M+H]⁺; 3.40 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.50-7.42 (m, 1H), 6.90-6.79 (m, 2H), 5.47(s, 2H), 5.47-5.41 (m, 1H), 5.20 (s, 1H), 4.99 (d, J=11.1 Hz, 1H), 4.61(d, J=8.7 Hz, 1H), 4.15-4.02 (m, 3H), 4.95 (d, J=11.4 Hz, 1H), 3.80-3.71(m, 1H), 2.04-1.90 (m, 1H), 1.67-1.53 (m, 1H).

E178(R)-6-((3-(((2-(trifluoromethyl)pyridin-4-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)methoxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

To a solution of(3-(((2-(trifluoromethyl)pyridin-4-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)methanol(15 mg, 0.055 mmol) in dry DMF (2 mL) was added NaH (60% in mineral oil,5 mg, 0.110 mmol) at 10° C. and the mixture was stirred for 20 min. Then(R)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(12 mg, 0.055 mmol) was added and the reaction was stirred at roomtemperature for overnight. The mixture was diluted with ice-water (5mL), extracted with EA (10 mL×2). The organic phases were dried overNa₂SO₄, filtered and concentrated. The residue was purified by prep-TLC(DCM/MeOH=20/1) to give the title compound (4 mg, yield 16%) as a whitesolid.

LC-MS (ESI): m/z 451 [M+H]⁺; 3.81 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 8.52 (d, J=5.7 Hz, 1H), 7.18 (d, J=2.1 Hz,1H), 6.95-6.92 (m, 1H), 5.31 (s, 1H), 4.98 (d, J=5.7 Hz, 1H), 4.58 (d,J=5.7 Hz, 1H), 4.40 (s, 2H), 4.26-4.17 (m, 3H), 4.09 (s, 3H), 3.52-3.49(m, 1H), 1.85 (s, 6H).

E179(S)-6-((3-(((2-(trifluoromethyl)pyridin-4-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)methoxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

To a solution of(3-(((2-(trifluoromethyl)pyridin-4-yl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)methanol(15 mg, 0.055 mmol) in dry DMF (2 mL) was added NaH (60% in mineral oil,5 mg, 0.110 mmol) at 10° C. and the mixture was stirred for 20 min. Then(S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(12 mg, 0.055 mmol) was added and the mixture was stirred at roomtemperature for overnight. The mixture was diluted with ice-water (5 mL)and extracted with EA (10 mL×2). The organic phases were dried overNa₂SO₄, filtered and concentrated. The residue was purified by prep-TLC(DCM/MeOH=20/1) to give the title compound (7 mg, yield 16%) as a whitesolid.

LC-MS (ESI): m/z 451 [M+H]⁺; 3.80 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 8.52 (d, J=5.1 Hz, 1H), 7.18 (d, J=2.1 Hz,1H), 6.95-6.92 (m, 1H), 5.32 (s, 1H), 4.98 (d, J=5.7 Hz, 1H), 4.58 (d,J=5.7 Hz, 1H), 4.40 (s, 2H), 4.26-4.17 (m, 3H), 4.09 (s, 3H), 3.52-3.47(m, 1H), 1.86 (s, 6H).

E180(S)-3-((2,4-difluorobenzyl)oxy)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(S)-3-chloro-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one(50 mg, 0.20 mmol) and (2,4-difluorophenyl)methanol (32 mg, 0.22 mmol)as a white solid.

LC-MS (ESI): m/z 336 [M+H]⁺; 3.40 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.49-7.42 (m, 1H), 6.89-6.79 (m, 2H), 5.42(t, J=3.0 Hz, 2H), 5.20 (s, 1H), 5.01 (d, J=11.1 Hz, 1H), 4.61 (d,J=10.8 Hz, 1H), 4.17-4.02 (m, 3H), 3.96 (t, J=9.9 Hz, 1H), 3.80-3.71 (m,1H) 1.99-1.92 (m, 1H), 1.67-1.58 (m, 1H).

E181(S)-3-((2,4,5-trifluorobenzyl)oxy)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(S)-3-chloro-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one(50 mg, 0.20 mmol) and (2,4,5-trifluorophenyl)methanol (36 mg, 0.22mmol) as a white solid.

LC-MS (ESI): m/z 354 [M+H]⁺; 3.58 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.35-7.29 (m, 1H), 6.98-6.89 (m, 1H),5.46-5.40 (m, 2H), 5.22 (s, 1H), 5.02 (d, J=11.4 Hz, 1H), 4.63 (d,J=11.4 Hz, 1H), 4.19-4.03 (m, 3H), 3.97-3.92 (m, 1H), 3.81-3.72 (m, 1H),2.00-1.94 (m, 1H), 1.68-1.63 (m, 1H).

E182(S)-3-((3,5-difluorobenzyl)oxy)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(S)-3-chloro-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one(50 mg, 0.20 mmol) and (3,5-difluorophenyl)methanol (32 mg, 0.22 mmol)as a white solid.

LC-MS (ESI): m/z 336 [M+H]⁺; 3.55 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 6.95-6.91 (m, 2H), 6.78-6.72 (m, 1H),5.45-5.35 (m, 2H), 5.28 (s, 1H), 5.06 (d, J=11.1 Hz, 1H), 4.65 (d,J=11.7 Hz, 1H), 4.18-4.05 (m, 3H), 3.99-3.95 (m, 1H), 3.83-3.75 (m, 1H),2.06-1.95 (m, 1H), 1.70-1.65 (m, 1H).

E183(S)-3-((2,3-difluorobenzyl)oxy)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(S)-3-chloro-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one(50 mg, 0.20 mmol) and (2,3-difluorophenyl)methanol (32 mg, 0.22 mmol)as a white solid.

LC-MS (ESI): m/z 336 [M+H]⁺; 3.46 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.25-7.19 (m, 1H), 7.15-7.04 (m, 2H),5.48-5.47 (m, 2H), 5.22 (s, 1H), 5.01 (d, J=11.4 Hz, 1H), 4.61 (d,J=11.4 Hz, 1H), 4.17-4.02 (m, 4H), 3.80-3.72 (m, 1H), 1.98-1.92 (m, 1H),1.67-1.62 (m, 1H).

E1846-((3,5-Difluorobenzyl)oxy)-10,10a-dihydro-2H-oxazolo[3′,2′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

A mixture of10,10a-dihydro-2H-oxazolo[3′,2′:3,4]imidazo[1,2-c]pyrimidine-6,8(3H,7H)-dione(195 mg, 1.0 mmol) and Ag₂CO₃ (688 mg, 2.5 mmol) in toluene (5 mL) washeated to 70° C. 1-(bromomethyl)-3,5-difluorobenzene (288 mg, 1.1 mmol)was then added and the mixture was stirred at 100° C. for overnight. Themixture was cooled to room temperature and filtered. The filtrate wasconcentrated and purified by prep-TLC (DCM/MeOH=30/1) to give the titlecompound (80 mg, yield 25%) as a yellow solid.

LC-MS (ESI): m/z 322 [M+H]⁺; 3.57 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 6.94-6.90 (m, 2H), 6.78-6.72 (m, 1H), 5.38(d, J=3.0 Hz 1H), 5.18 (s, 2H), 5.17 (d, J=4.5 Hz 1H), 4.35-4.30 (s,1H), 4.16-3.87 (s, 3H), 3.56 (t, J=6.9 Hz 2H).

E185(R)-6-(3-fluorophenethoxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(R)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(50 mg, 0.23 mmol) and 2-(3-fluorophenyl)ethanol (36 mg, 0.26 mmol) as awhite solid.

LC-MS (ESI): m/z 318 [M+H]⁺; 3.54 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.26-7.24 (m, 1H), 7.02-6.91 (m, 3H), 5.26(s, 1H), 4.56 (d, J=6.3 Hz, 1H), 4.60-4.55 (m, 3H), 4.24-4.06 (m, 4H),3.50-3.45 (m, 1H), 3.02 (t, J=6.6 Hz, 2H).

E186(S)-6-(3-fluorophenethoxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(50 mg, 0.23 mmol) and 2-(3-fluorophenyl)ethanol (36 mg, 0.26 mmol) as awhite solid.

LC-MS (ESI): m/z 318 [M+H]⁺; 3.54 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.29-7.24 (m, 1H), 7.02-6.91 (m, 3H), 5.26(s, 1H), 4.95 (d, J=5.7 Hz, 1H), 4.59-4.55 (m, 3H), 4.24-4.08 (m, 4H),3.50-3.45 (m, 1H), 3.02 (t, J=6.9 Hz, 2H).

E1876-((2,3-Difluorobenzyl)oxy)-10,10a-dihydro-2H-oxazolo[3′,2′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

A mixture of10,10a-dihydro-2H-oxazolo[3′,2′:3,4]imidazo[1,2-c]pyrimidine-6,8(3H,7H)-dione(195 mg, 1.0 mmol) and Ag₂CO₃ (828 mg, 3.0 mmol) in toluene (10 mL) washeated to 70° C. 1-(Bromomethyl)-2,3-difluorobenzene (621 mg, 3.0 mmol)was then added and the mixture was stirred at 110° C. for 2 days. Themixture was cooled to room temperature, filtered. The filtrate wasconcentrated and purified by prep-TLC (DCM/MeOH=30/1) to give a whitesolid, which was further purified by prep-HPLC to give the titlecompound (40 mg, yield 12%) as a yellow solid.

LC-MS (ESI): m/z 322 [M+H]⁺; 3.49 min (ret time).

¹H NMR (300 MHz, DMSO-d₆): δ 7.92-7.23 (m, 3H), 7.68 (s, 1H), 5.42 (s,2H), 5.19 (d, J=4.5 Hz, 1H), 4.14-3.38 (m, 6H).

E1886-((3,4,5-Trifluorobenzyl)oxy)-10,10a-dihydro-2H-oxazolo[3′,2′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

A mixture of10,10a-dihydro-2H-oxazolo[3′,2′:3,4]imidazo[1,2-c]pyrimidine-6,8(3H,7H)-dione(195 mg, 1.0 mmol) and Ag₂CO₃ (828 mg, 3.0 mmol) in toluene (10 mL) washeated to 70° C. 5-(Bromomethyl)-1,2,3-trifluorobenzene (675 mg, 3.0mmol) was added and the mixture was stirred at 110° C. for 2 days. Themixture was cooled to room temperature, and filtered. The filtrate wasconcentrated and purified by prep-TLC DCM/MeOH=30/1 to give a whitesolid, which was further purified by prep-HPLC to give the titlecompound (78 mg, yield 23%) as a white solid.

LC-MS (ESI): m/z 340 [M+H]⁺; 3.68 min (ret time).

¹H NMR (300 MHz, DMSO-d₆): δ 7.43-7.39 (m, 2H), 5.70 (s, 1H), 5.27 (s,2H), 5.19 (d, J=4.2 Hz 1H), 4.14-3.80 (m, 4H), 3.69-3.27 (m, 2H).

E189 and E190 E189: Enantiomer 1:6-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-10,10a-dihydro-2H-oxazolo[3′,2′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(E189) E190: Enantiomer 2:6-((3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-10,10a-dihydro-2H-oxazolo[3′,2′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(E190)

A mixture of10,10a-dihydro-2H-oxazolo[3′,2′:3,4]imidazo[1,2-c]pyrimidine-6,8(3H,7H)-dione(120 mg, 0.615 mmol) and Ag₂CO₃ (423 mg, 1.538 mmol) in toluene (5 mL)was heated to 70° C.4-(4-(Bromomethyl)-2,6-difluorophenoxy)-1-methyl-1H-pyrazole (224 mg,0.738 mmol) was then added and the mixture was stirred at 110° C. forovernight. The mixture was cooled to room temperature, filtered. Thefiltrate was concentrated. The residue was purified by prep-HPLC to givea white solid, which was further purified by chiral HPLC to give thetitle compounds enantiomer 1 (21 mg, yield 8%) as yellow oil andenantiomer 2 (17 mg, yield 8%) as a yellow solid.

Enantiomer 1

LC-MS (ESI): m/z 418 [M+H]⁺; 3.42 min (ret time).

¹H NMR (300 MHz, CD₃OD): δ 7.42 (s, 1H), 7.22-7.16 (m, 3H), 5.63 (s,1H), 5.33 (s, 2H), 5.23-4.87 (m, 1H), 4.16 (s, 2H), 4.16-4.00 (m, 1H),3.98-3.92 (m, 1H), 3.84 (s, 3H), 3.67-3.64 (m, 1H), 3.66-3.56 (m, 1H).

Enantiomer 2

LC-MS (ESI): m/z 418 [M+H]⁺; 3.42 min (ret time).

¹H NMR (300 MHz, CD₃OD): δ 7.42 (s, 1H), 7.22-7.16 (m, 3H), 5.63 (s,1H), 5.33 (s, 2H), 5.24-5.22 (m, 1H), 4.16 (s, 2H), 4.16-4.00 (m, 1H),3.98-3.92 (m, 1H), 3.84 (s, 3H), 3.67-3.64 (m, 1H), 3.66-3.56 (m, 1H).

E191(S)-4-(2-((8-oxo-3,8,10,10a-tetrahydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-6-yl)oxy)ethyl)benzonitrile

To a solution of(S)-6-(4-bromophenethoxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(40 mg, 0.11 mmol) in DMF (4 mL) was added Zn(CN)₂ (26 mg, 0.22 mmol)and Pd(PPh₃)₄ (10 mg) under N₂. The reaction mixture was stirred at 150°C. in a microwave instrument for 20 min. The reaction mixture wasconcentrated and purified by prep-HPLC to give the title compound (20mg, yield 56%) as a white solid.

LC-MS (ESI): m/z 325 [M+H]⁺; 3.24 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.59 (d, J=8.1 Hz, 2H), 7.36-7.26 (m, 2H),5.23 (s, 1H), 4.95 (d, J=5.4 Hz, 1H), 4.62-4.55 (m, 3H), 4.25-4.06 (m,4H), 3.51-3.46 (m, 1H), 3.11-3.07 (m, 2H).

E192(R)-3-(3-fluorophenethyl)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one

A solution of(R)-3-((3-fluorophenyl)ethynyl)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one (25 mg, 0.08 mmol) and 10% wet Pd/C (3 mg)in MeOH (3 mL) was stirred for 2 hours at room temperature under H₂ (1atm). The mixture was filtered and the filtrate was evaporated. Theresidue was purified by TLC (DCM/MeOH=20/1) to give title compound (17mg, yield 65%) as a light yellow solid.

LC-MS (ESI): m/z 316 [M+H]⁺; 2.58 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.26-7.19 (m, 1H), 7.00-6.88 (m, 3H), 5.53(s, 1H), 5.05 (d, J=11.4 Hz, 1H), 4.63 (d, J=11.4 Hz, 1H), 4.18-4.08 (m,3H), 4.01-3.98 (m, 1H), 3.82-3.73 (m, 1H), 3.07-3.01 (m, 2H), 2.82-2.77(m, 2H), 1.99-1.89 (m, 2H), 1.70-1.65 (m, 1H).

E193(R)-6-((3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)phenyl)methanol (40 mg,0.16 mmol) and(R)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(34 mg, 0.16 mmol) as a white solid.

LC-MS (ESI): m/z 424 [M+H]⁺; 4.09 min (ret time).

¹H NMR (400 MHz, CDCl₃): δ 6.97-6.92 (m, 2H), 5.34-5.26 (m, 3H), 4.97(d, J=6.0 Hz, 1H), 4.83 (t, J=6.4 Hz, 1H), 4.71 (t, J=6.4 Hz, 1H), 4.58(d, J=5.6 Hz, 1H), 4.29-4.07 (m, 4H), 3.52-3.48 (m, 1H), 2.18-2.09 (m,2H), 1.08 (t, J=6.8 Hz, 2H), 0.67-0.63 (m, 2H).

E194(R)-6-((9-fluoro-3,4-dihydrospiro[benzo[b][1,4]dioxepine-2,1′-cyclopropan]-7-yl)methoxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)phenyl)methanol (40 mg,0.16 mmol) and(R)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(34 mg, 0.16 mmol) as yellow oil.

LC-MS (ESI): m/z 402 [M+H]⁺; 3.56 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 6.84-6.80 (m, 2H), 5.34-5.23 (m, 3H), 4.97(d, J=5.7 Hz, 1H), 4.59 (d, J=6.0 Hz, 1H), 4.30-4.07 (m, 6H), 3.53-3.48(m, 1H), 2.21 (t, J=5.1 Hz, 2H), 1.08-1.04 (m, 2H), 0.63-0.53 (m, 2H).

E195(R)-3-((3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)benzyl)oxy)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)phenyl)methanol (40 mg,0.16 mmol) and(R)-3-chloro-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one(36 mg, 0.16 mmol) as colorless oil.

LC-MS (ESI): m/z 438 [M+H]⁺; 3.14 min (ret time).

¹H NMR (400 MHz, CDCl₃): δ 6.97-6.22 (m, 2H), 5.35-5.29 (m, 2H), 5.22(s, 1H), 5.04-5.00 (m, 1H), 4.85 (d, J=6.3 Hz, 1H), 4.71-4.60 (m, 2H),4.16-3.71 (m, 5H), 2.18-2.07 (m, 2H), 1.97-1.92 (m, 1H), 1.68-1.62 (m,1H), 1.09-1.62 (t, J=6.6 Hz, 2H), 0.66-0.62 (t, J=6.0 Hz, 2H).

E196(R)-3-((9-fluoro-3,4-dihydrospiro[benzo[b][1,4]dioxepine-2,1′-cyclopropan]-7-yl)methoxy)-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)phenyl)methanol (40 mg,0.16 mmol) and(R)-3-chloro-8,9,9a,10-tetrahydropyrimido[6′,1′:2,3]imidazo[1,5-c][1,3]oxazin-1(6H)-one(36 mg, 0.16 mmol) as colorless oil.

LC-MS (ESI): m/z 416 [M+H]⁺; 3.03 min (ret time).

¹H NMR (400 MHz, CDCl₃): δ 6.84-6.79 (m, 2H), 5.32-5.22 (m, 3H), 5.01(d, J=10.5 Hz, 1H), 4.02 (d, J=11.1 Hz, 1H), 4.26-4.22 (m, 2H),4.15-3.72 (m, 5H), 2.20 (t, J=5.7 Hz, 2H), 1.98-1.92 (m, 1H), 1.66 (s,1H), 1.07-1.03 (m, 2H), 0.62-0.57 (m, 2H).

E197(S)-6-((3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)benzyl)oxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)phenyl)methanol (40 mg,0.16 mmol) and(S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(34 mg, 0.16 mmol) as a white solid.

LC-MS (ESI): m/z 424 [M+H]⁺; 4.09 min (ret time).

¹H NMR (400 MHz, CDCl₃): δ 6.93 (d, J=8.4 Hz, 2H), 5.33-5.28 (m, 3H),4.96 (d, J=5.7 Hz, 1H), 4.84 (t, J=6.3 Hz, 1H), 4.68 (t, J=6.0 Hz, 1H),4.56 (t, J=5.7 Hz, 1H), 4.29-4.06 (m, 4H), 3.52-3.47 (m, 1H), 2.18-2.06(m, 2H), 1.06 (t, J=6.6 Hz, 2H), 0.64 (t, J=6.6 Hz, 2H).

E198(S)-6-((9-fluoro-3,4-dihydrospiro[benzo[b][1,4]dioxepine-2,1′-cyclopropan]-7-yl)methoxy)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)phenyl)methanol (40 mg,0.16 mmol) and(S)-6-chloro-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(36 mg, 0.16 mmol) as yellow oil.

LC-MS (ESI): m/z 402 [M+H]⁺; 3.80 min (ret time).

¹H NMR (400 MHz, CDCl₃): δ 6.87-6.83 (m, 2H), 5.37-5.26 (m, 3H), 4.99(d, J=5.4 Hz, 1H), 4.61 (d, J=5.7 Hz, 1H), 4.32-4.10 (m, 6H), 3.56-3.51(m, 1H), 2.24 (t, J=6.0 Hz, 2H), 1.09 (t, J=6.0 Hz, 2H), 0.66-0.61 (m,2H).

E1997-((3,5-Difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)benzyl)oxy)-2-methyl-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

The title compound was prepared by a procedure similar to that describedfor E141 starting from(3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)phenyl)methanol (47 mg,0.19 mmol) and7-chloro-2-methyl-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one(45 mg, 0.19 mmol) as yellow oil.

LC-MS (ESI): m/z 451 [M+H]⁺; 3.97 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 6.93 (d, J=8.4 Hz, 2H), 5.28 (s, 2H), 5.00(s, 1H), 4.84 (t, J=6.0 Hz, 1H), 4.69 (t, J=6.3 Hz, 1H), 4.17-4.11 (m,1H), 4.02-4.01 (m, 1H), 3.74-3.68 (m, 1H), 3.46-3.29 (m, 2H), 2.92-2.88(m, 1H), 2.78-2.74 (m, 1H), 2.32 (s, 3H), 2.18-1.90 (m, 4H), 1.06 (t,J=6.9 Hz, 2H), 0.63 (t, J=6.6 Hz, 2H).

E2007-((3,5-Difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-3,4,11,11atetrahydro pyrimido[6′,1′:2,3]imidazo[5,1-b][1,3]oxazin-9(2H)-one

A mixture of3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-b][1,3]oxazine-7,9(2H,8H)-dione(80 mg, 0.383 mmol) and Ag₂CO₃ (263 mg, 0.958 mmol) in toluene (5 mL)was stirred at 70° C. for 40 minutes.4-(4-(Bromomethyl)-2,6-difluorophenoxy)-1-methyl-1H-pyrazole (128 mg,0.421 mmol) was then added and the mixture was stirred at 110° C. forovernight. The mixture was filtered, concentrated in vacuo. The residuewas purified by prep-TLC (DCM/MeOH=25/1) to give the title compound (56mg, yield 34%) as a white solid.

LC-MS (ESI): m/z 432 [M+H]⁺; 3.47 min (ret time).

¹H NMR (300 MHz, CD₃OD): δ 7.33 (s, 1H), 7.13-7.05 (m, 3H), 5.40 (d,J=5.1 Hz, 1H) 5.26 (d, J=1.5 Hz, 3H) 3.99-3.91 (m, 2H), 3.83-3.79 (m,3H), 3.75-3.66 (m, 3H), 3.52-3.42 (m, 1H), 1.47-1.41 (m, 1H), 1.19 (d,J=5.4 Hz, 1H).

E201(S)-6-(3-fluorophenethyl)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

A solution of(S)-6-((3-fluorophenyl)ethynyl)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(30 mg, 0.10 mmol) and 10% wet Pd/C (3 mg) in MeOH (3 mL) was stirredfor 2 hrs at room temperature under H₂ (1 atm). The mixture was filteredand the filtrate was evaporated. The residue was purified by prep TLC(DCM/MeOH=25/1) to give title compound (25 mg, yield 85%) as a whitesolid.

LC-MS (ESI): m/z 302 [M+H]⁺; 2.58 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.26-7.19 (m, 1H), 7.00-6.86 (m, 3H), 5.59(s, 1H), 4.93 (d, J=5.7 Hz, 1H), 4.57 (d, J=5.7 Hz, 1H), 4.30-4.20 (m,3H), 4.13-4.08 (m, 1H), 3.53-3.48 (m, 1H), 3.08-3.02 (m, 2H), 2.86-2.81(m, 2H).

E202(S)-6-(2,4-difluorophenethyl)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one

A solution of(S)-6-((2,4-difluorophenyl)ethynyl)-10,10a-dihydro-1H-oxazolo[3′,4′:3,4]imidazo[1,2-c]pyrimidin-8(3H)-one(50 mg, 0.16 mmol) and 10% wet Pd/C (4 mg) in MeOH (5 mL) was stirredfor 2 hrs at room temperature under H₂ (1 atm). The mixture was filteredand the filtrate was evaporated. The residue was purified by prep HPLC(Column: XB C18, 4.6×33 mm; Mobile phase: A: H₂O, B: MeCN, 20-95% B) togive the title compound (30 mg, yield 60%) as a white solid.

LC-MS (ESI): m/z 320 [M+H]⁺; 3.29 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.17-7.12 (m, 1H), 6.81-6.74 (m, 2H), 5.62(s, 1H), 4.95 (d, J=6.0 Hz, 1H), 4.57 (d, J=6.0 Hz, 1H), 4.30-4.23 (m,3H), 4.13-4.08 (m, 1H), 3.53-3.48 (m, 1H), 3.06-3.01 (m, 2H), 2.84-2.79(m, 2H).

E2033-((4-(Methylsulfonyl)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from (4-(methylsulfonyl)phenyl)methanol and3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 376 [M+H]⁺; 1.78 min (ret time).

E2043-((4-Fluoro-3-(methylsulfonyl)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H0pyrido[1′,2′:3,4]imidazo-[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from (4-fluoro-3-(methylsulfonyl)phenyl)methanol and3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 394 [M+H]⁺; 1.88 min (ret time).

E205(S)-3-((4-((3,3-difluoropiperidin-1-yl)methyl)-3-fluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from(4-((3,3-difluoropiperidin-1-yl)methyl)-3-fluorophenyl)methanol and(S)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 449 [M+H]⁺; 1.64 min (ret time).

¹HNMR (400 MHZ, CD₃OD): δ 7.43 (t, 1H), 7.21 (q, 2H), 5.34 (s, 2H), 5.29(s, 1H), 4.20 (q, 1H), 3.94-3.85 (m, 1H), 3.73-3.69 (m, 1H), 3.69 (s,2H), 3.62 (q, 1H), 3.06 (dt, 1H), 2.65 (t, 2H), 2.51 (t, 2H), 2.02-1.75(m, 7H), 1.60-1.49 (m, 3H).

E206(S)-3-((4-((4,4-difluorocyclohexyl)oxy)-3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo [1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (S)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(4-((4,4-difluorocyclohexyl)oxy)-3,5-difluorophenyl)methanol.

LC-MS (ESI): m/z 454 [M+H]⁺; 2.92 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.23-7.21 (d, 1H), 5.32 (s, 1H), 5.23-5.18(q, 2H), 4.38 (s, 1H), 3.4.09-4.00 (m, 2H), 3.87-3.83 (m, 1H), 3.50-3.27(m, 2H), 2.16-1.76 (m, 11H), 1.48-1.39 (m, 1H).

E207(S)-3-((4-((1-butylazetidin-3-yl)oxy)-3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (S)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(4-((1-butylazetidin-3-yl)oxy)-3,5-difluorophenyl)methanol.

LC-MS (ESI): m/z 447 [M+H]⁺; 2.06 min (ret time).

¹HNMR (400 MHZ, CD₃OD): δ 7.12-7.10 (d, 2H), 5.35-5.24 (m, 3H),4.79-4.76 (s, 1H), 4.18-4.14 (m, 2H), 4.00-3.96 (m, 1H), 3.73-3.70 (m,2H), 3.31-3.27 (m, 4H), 2.57-2.53 (s, 2H), 2.15-1.99 (m, 3H), 1.56-1.49(m, 1H), 1.40-1.31 (m, 4H), 0.87-0.84 (m, 3H).

E208(S)-3-((3,5-difluoro-4-(3-fluoropropyl)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (S)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3,5-difluoro-4-(3-fluoropropyl)phenyl)methanol.

LC-MS (ESI): m/z 380 [M+H]⁺; 2.61 min (ret time).

¹H NMR (400 MHz, DMSO-d₆): δ 7.13-7.11 (d, 2H), 5.34 (s, 1H), 5.26-5.21(m, 2H), 4.54-4.39 (m, 2H), 4.04-4.00 (m, 2H), 3.87-3.85 (m, 1H),3.30-3.28 (m, 2H), 2.74-2.68 (m, 2H), 2.05-1.80 (m, 5H), 1.48-1.38 (m,1H).

E2093-((3,5-Difluoro-4-(2-fluoroethoxy)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from 3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3,5-difluoro-4-(2-fluoroethoxy)phenyl)methanol.

LC-MS (ESI): m/z 382 [M+H]⁺; 2.48 min (ret time).

E210(S)-3-((3,5-difluoro-4-(2-fluoroethoxy)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (S)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3,5-difluoro-4-(2-fluoroethoxy)phenyl)methanol.

LC-MS (ESI): m/z 382 [M+H]⁺; 2.48 min (ret time).

E211 (S)-(1-(2,6-dichloropyrimidin-4-yl)pyrrolidin-2-yl)methanol

The title compound was prepared by a procedure similar to that describedfor E63 starting from (R)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(2,4-difluoro-phenyl)methanol.

LC-MS (ESI): m/z 320 [M+H]⁺; 3.65 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.46 (q, 1H), 6.89-6.78 (m, 2H), 5.40 (q,2H), 5.08 (s, 1H), 4.21-4.00 (m, 3H), 3.43-3.35 (m, 1H), 3.28-3.20 (m,1H), 2.18-1.93 (m, 3H), 1.51-1.37 (m, 1H).

E212(S)-3-((2,3-difluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (S)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(2,3-difluoro-phenyl)methanol.

LC-MS (ESI): m/z 320 [M+H]⁺; 3.69 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.24-7.02 (m, 3H), 5.51-5.41 (m, 2H), 5.10(s, 1H), 4.21-4.01 (m, 3H), 3.44-3.36 (m, 1H), 3.29-3.21 (m, 1H),2.19-1.96 (m, 3H), 1.51-1.41 (m, 1H).

E213(S)-3-((2,4,5-trifluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (S)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(2,4,5-trifluoro-phenyl)methanol.

LC-MS (ESI): m/z 338 [M+H]⁺; 3.81 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.35-7.29 (m, 1H), 6.97-6.86 (m, 1H),5.44-5.30 (m, 2H), 5.10 (s, 1H), 4.21-3.98 (m, 3H), 3.45-3.34 (m, 1H),3.30-3.20 (m, 1H), 2.19-1.95 (m, 3H), 1.52-1.38 (m, 1H).

E214(S)-3-((3-fluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (S)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3-fluorophenyl)methanol.

LC-MS (ESI): m/z 302 [M+H]⁺; 3.63 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.35-7.30 (m, 1H), 7.17-7.10 (m, 2H),7.03-6.96 (m, 1H), 5.44-5.33 (m, 2H), 5.12 (s, 1H), 4.21-4.01 (m, 3H),3.45-3.37 (m, 1H), 3.30-3.21 (m, 1H), 2.19-1.94 (m, 3H), 1.52-1.38 (m,1H).

E215(S)-3-((3,5-difluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (S)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3,5-difluorophenyl)methanol.

LC-MS (ESI): m/z 320 [M+H]⁺; 3.78 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 6.94-6.89 (m, 2H), 6.77-6.69 (m, 1H),5.43-5.31 (m, 2H), 5.14 (s, 1H), 4.21-4.02 (m, 3H), 3.46-3.38 (m, 1H),3.32-3.23 (m, 1H), 2.20-1.95 (m, 3H), 1.53-1.39 (m, 1H).

E216(R)-3-((2,4-difluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E104 starting from (R)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(2,4-difluorophenyl)methanamine.

LC-MS (ESI): m/z 319[M+H]⁺; 3.21 min (ret time).

¹H NMR (300 MHz, CD₃OD-d₄): δ 7.47-7.41 (m, 1H), 7.00-6.91 (m, 2H),5.07-5.06 (m, 1H), 4.54-4.51 (m, 2H), 4.18-4.09 (m, 2H), 3.91-3.90 (m,1H), 3.44-3.41 (m, 1H), 2.17-1.99 (m, 3H), 1.50-1.46 (m, 1H), 0.92-0.85(m, 1H).

E217(R)-3-((3,5-difluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E104 starting from (R)-3-chloro-7, 8, 8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(3,4-difluorophenyl)methanamine.

LC-MS (ESI): m/z 319 [M+H]⁺; 3.22 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 6.85-6.81 (m, 2H), 6.70-6.64 (m, 1H),4.73-4.58 (m, 3H), 4.14-4.07 (m, 1H), 4.01-3.96 (m, 2H), 3.39-3.31 (m,1H), 3.19-3.16 (m, 1H), 2.15-1.94 (m, 3H), 1.45-1.38 (m, 1H).

E218(R)-3-((2,4,5-trifluorobenzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from (R)-3-chloro-7, 8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one and(2,4,5-trifluorophenyl)methanol.

LC-MS (ESI): m/z 338[M+H]⁺; 3.75 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.35-7.28 (m, 1H), 6.97-6.89 (m, 1H),5.44-5.33 (m, 2H), 5.10 (s, 1H), 4.21-4.02 (m, 3H), 3.45-3.37 (m, 1H),3.30-3.21 (m, 1H), 2.18-1.98 (m, 3H), 1.52-1.41 (m, 1H).

E219(R)-7-((2,4,5-trifluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(R)-7-chloro-1-ethyl-2-(methoxymethyl)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (2,4, 5-trifluorophenyl)methanol.

LC-MS (ESI): m/z 354 [M+H]⁺; 3.41 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.35-7.28 (m, 1H), 6.98-6.90 (m, 1H), 5.40(s, 2H), 5.01 (s, 1H), 4.20-3.91 (m, 4H), 3.71-3.65 (m, 1H), 3.58-3.34(m, 4H).

E220(S)-7-((2,4,5-trifluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(S)-7-chloro-1-ethyl-2-(methoxymethyl)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (2,4, 5-trifluorophenyl)methanol.

LC-MS (ESI): m/z 354 [M+H]⁺; 3.41 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.35-7.28 (m, 1H), 6.97-6.89 (m, 1H), 5.39(t, J=13.2 Hz, 2H), 5.01 (s, 1H), 4.19-3.91 (m, 4H), 3.70-3.65 (m, 1H),3.58-3.33 (m, 4H).

E221(R)-7-((2,3-difluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(R)-7-chloro-1-ethyl-2-(methoxymethyl)-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-oneand (2,4, difluorophenyl)methanol.

LC-MS (ESI): m/z 336 [M+H]⁺; 3.32 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.25-7.03 (m, 3H), 5.47 (t, J=12.6 Hz, 2H),5.01 (s, 1H), 4.19-3.89 (m, 4H), 3.70-3.64 (m, 1H), 3.58-3.32 (m, 4H).

E222(R)-3-((3,5-difluorobenzyl)(methyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

To a solution of(R)-3-((3,5-difluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo [1′,2′:3,4]imidazo [1,2-c] pyrimidin-1(6H)-one (47 mg, 0.15 mmol) and potassiumcarbonate (61 mg, 0.44 mmol) in N, N-dimethylformamide (2 mL) was addediodomethane (42 mg, 0.30 mmol) at room temperature. The reaction mixturewas stirred at room temperature for 2 days. The reaction mixture waspoured into water (10 mL), extracted with EA (20 mL) twice. The combinedorganic layers was washed with water, brine and dried over anhydroussodium sulfate, concentrated under reduced pressure and purified byprep-TLC (DCM/MeOH=15/1) to give the title compound (40 mg, yield 82%)as a white solid.

LC-MS (ESI): m/z 333 [M+H]⁺; 2.96 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.02-7.00 (m, 2H), 6.72-6.66 (m, 1H), 4.88(s, 1H), 4.73 (s, 2H), 4.30-4.19 (m, 2H), 3.99-3.96 (m, 1H), 3.80 (s,3H), 3.51-3.44 (m, 1H), 3.28-3.24 (m, 1H), 2.28-2.08 (m, 3H), 1.57-1.51(m, 1H).

E223(R)-3-((2,4-difluorobenzyl)(methyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E222 starting from(R)-3-((2,4-difluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-(6H)-oneand iodomethane.

LC-MS (ESI): m/z 333 [M+H]⁺; 2.88 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.58-7.56 (m, 1H), 6.87-6.76 (m, 2H), 4.77(s, 1H), 4.34 (s, 2H), 4.07-4.04 (m, 1H), 3.97-3.84 (m, 2H), 3.39-3.33(m, 4H), 3.23-3.20 (m, 1H), 2.13-1.97 (m, 3H), 1.40-1.25 (m, 1H).

E224(S)-3-(3-fluorophenethyl)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

To a solution of(S)-3-((3-fluorophenyl)ethynyl)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one(30 mg, 0.10 mmol) in methanol (5 mL) was added 10% Pd/C (3 mg). Thereaction mixture was stirred at room temperature overnight underhydrogen and then filtered. The filtrate was evaporated under reducedpressure and purified by TLC (MeOH/DCM=1/30) to give the title compound(22 mg, 73%) as a yellow oil.

LC-MS (ESI): m/z 300 [M+H]⁺; 3.32 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.23-7.18 (m, 1H), 7.00-6.84 (m, 3H), 5.40(s, 1H), 4.22-4.06 (m, 3H), 3.41-3.36 (m, 1H), 3.29-3.23 (m, 1H),3.07-3.01 (m, 2H), 2.81-2.76 (m, 2H), 2.19-1.99 (m, 2H), 1.51-1.47 (m,1H).

E225(R)-3-((2,4,5-trifluorobenzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E1 starting from (2,4,5-trifluorophenyl)methanol and(R)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 352 [M+H]⁺; 4.00 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.34-7.28 (m, 1H), 6.96-6.90 (m, 1H), 5.39(s, 2H), 4.97 (s, 1H), 4.24-4.19 (m, 1H), 3.79-3.76 (m, 1H), 3.69-3.65(m, 1H), 3.55-3.51 (m, 1H), 3.00 (t, J=6.9 Hz, 1H), 1.96 (t, J=4.5 Hz,2H), 1.76 (t, J=4.8 Hz, 1H), 1.59-1.47 (m, 3H).

E226(S)-3-((2,4,5-trifluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E104 starting from(S)-3-chloro-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-oneand (2,4,5-trifluorophenyl)methanamine.

LC-MS (ESI): m/z 337 [M+H]⁺; 3.35 min (ret time).

¹H NMR (300 MHz, CD₃OD-d₄): δ 7.38-7.28 (m, 1H), 7.18-7.09 (m, 1H), 5.07(s, 1H), 4.60-4.46 (m, 2H), 4.11-4.01 (m, 2H), 3.93-3.85 (m, 1H),3.43-3.35 (m, 1H), 3.32-3.22 (m, 1H), 2.14-1.90 (m, 3H), 1.51-1.37 (m,1H).

E227(S)-3-((3,5-difluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E104 starting from(S)-3-chloro-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-oneand (3,5-difluorophenyl)methanamine.

LC-MS (ESI): m/z 319 [M+H]⁺; 3.31 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 6.85 (d, 2H), 6.70-6.63 (m, 1H), 4.74-4.59(m, 3H), 4.13-4.06 (m, 1H), 4.02-3.94 (m, 2H), 3.38-3.30 (m, 1H),3.22-3.12 (m, 1H), 2.14-1.84 (m, 3H), 1.48-1.34 (m, 1H).

E228(S)-3-((2,3-difluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E104 starting from (S)-3-chloro-7, 8, 8a, 9-tetrahydropyrrolo[1′,2′:3, 4]imidazo[1, 2-c]pyrimidin-1(6H)-one and (2,3-difluorophenyl)methanamine.

LC-MS (ESI): m/z 319 [M+H]⁺; 3.28 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.21-7.17 (m, 1H), 7.11-6.99 (m, 2H),4.77-4.61 (m, 3H), 4.15-4.07 (m, 1H), 4.01-3.93 (m, 2H), 3.39-3.33 (m,1H), 3.23-3.14 (m, 1H), 2.17-1.90 (m, 3H), 1.47-1.34 (m, 1H).

E229(S)-3-((3,4,5-trifluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E104 starting from (S)-3-chloro-7, 8, 8a, 9-tetrahydropyrrolo[1′,2′:3, 4]imidazo[1, 2-c]pyrimidin-1(6H)-one and(3,4,5-trifluorophenyl)methanamine.

LC-MS (ESI): m/z 337 [M+H]⁺; 3.42 min (ret time).

¹H NMR (300 MHz, CD₃OD-d₄): 6.95 (t, J=7.5 Hz, 2H), 4.74-4.48 (m, 3H),4.12-3.91 (m, 3H), 3.38-3.30 (m, 1H), 3.20-3.12 (m, 1H), 2.13-1.80 (m,3H), 1.48-1.34 (m, 1H).

E230(S)-3-((3-fluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E104 starting from (S)-3-chloro-7, 8, 8a, 9-tetrahydropyrrolo[1′,2′:3, 4]imidazo[1, 2-c]pyrimidin-1(6H)-one and(3-fluorophenyl)methanamine.

LC-MS (ESI): m/z 301 [M+H]⁺; 2.72 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.31-7.24 (m, 1H), 7.11-6.99 (m, 2H),6.96-6.91 (m, 1H), 4.76-4.67 (m, 1H), 4.60-4.50 (m, 2H), 4.13-4.05 (m,1H), 4.04-3.92 (m, 2H), 3.37-3.29 (m, 1H), 3.21-3.12 (m, 1H), 2.17-1.80(m, 3H), 1.47-1.26 (m, 1H).

E231(S)-3-((2,4-difluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E104 starting from (S)-3-chloro-7, 8, 8a, 9-tetrahydropyrrolo[1′,2′:3, 4]imidazo[1, 2-c]pyrimidin-1(6H)-one and(2,4-difluorophenyl)methanamine.

LC-MS (ESI): m/z 319 [M+H]⁺; 3.28 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.47-7.39 (m, 1H), 6.85-6.75 (m, 2H), 4.78(s, 1H), 4.67-4.52 (m, 2H), 4.14-4.05 (m, 1H), 4.02-3.92 (m, 2H),3.38-3.31 (m, 1H), 3.23-3.14 (m, 1H), 2.17-1.80 (m, 3H), 1.47-1.33 (m,1H).

E232(S)-3-((2,4-difluorobenzyl)amino)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

To a solution of(S)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one(100 mg, 0.44 mmol) and (2,4-difluorophenyl)methanamine (95 mg, 0.66mmol) in 1,4-dioxane (2 mL) was added DIEA (568 mg, 4.40 mmol) at roomtemperature. The reaction mixture was stirred at 100° C. overnight,concentrated under reduced pressure and purified with prep-HPLC to givethe title compound (92 mg, 63%) as a yellow solid.

LC-MS (ESI): m/z 333 [M+H]⁺; 2.94 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.45-7.38 (m, 1H), 6.86-6.75 (m, 2H),4.63-4.51 (m, 3H), 4.18-4.12 (m, 1H), 3.70-3.55 (m, 2H), 3.49-3.45 (m,1H), 2.97-2.88 (m, 1H), 2.03-1.63 (m, 3H), 1.57-1.35 (m, 3H).

E233 (S)-3-((3-fluorobenzyl)amino)-6,7,8,9,9a,10-hexahydro-1Hpyrido[1′,2′:3,4]imidazo[1,2-c] pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E232 starting from (3-fluorophenyl)methanamine and(S)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 315 [M+H]⁺; 2.86 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.29-7.22 (m, 1H), 7.09-6.88 (m, 3H), 4.58(d, J=10.8 Hz, 3H), 4.15-4.09 (m, 1H), 3.67-3.41 (m, 3H), 2.94-2.85 (m,1H), 2.00-1.66 (m, 3H), 1.52-1.38 (m, 3H).

E234(S)-3-((3,5-difluorobenzyl)amino)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E232 starting from (3,5-difluorophenyl)methanamine and(S)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 333 [M+H]⁺; 2.96 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 6.87-6.81 (m, 2H), 6.70-6.63 (m, 1H), 4.56(d, J=13.2 Hz, 3H), 4.18-4.12 (m, 1H), 3.74-3.55 (m, 2H), 3.49-3.43 (m,1H), 3.00-2.88 (m, 1H), 1.96-1.87 (m, 2H), 1.70-1.67 (m, 1H), 1.55-1.39(m, 3H).

E235(R)-3-((2,4,5-trifluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E232 starting from(R)-3-chloro-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-oneand (2,4,5-trifluorophenyl)methanamine.

LC-MS (ESI): m/z 337 [M+H]⁺; 2.83 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.35-7.29 (m, 1H), 6.93-6.84 (m, 1H), 4.76(s, 1H), 4.58 (br s, 2H), 4.14-4.07 (m, 1H), 4.03-3.95 (m, 2H),3.39-3.31 (m, 1H), 3.22-3.14 (m, 1H), 2.14-1.94 (m, 3H), 1.48-1.39 (m,1H).

E236(R)-3-((3,4,5-trifluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E104 starting from(R)-3-chloro-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-oneand (3,4,5-trifluorophenyl)methanamine.

LC-MS (ESI): m/z 337 [M+H]⁺; 3.46 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.01-6.93 (m, 2H), 4.70-4.54 (m, 3H),4.11-3.91 (m, 3H), 3.37-3.30 (m, 1H), 3.20-3.11 (m, 1H), 2.13-1.86 (m,3H), 1.47-1.34 (m, 1H).

E237(R)-3-((2,3-difluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E104 starting from(R)-3-chloro-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-oneand (2,3-difluorophenyl)methanamine.

LC-MS (ESI): m/z 319 [M+H]⁺; 3.34 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.23-7.18 (m, 1H), 7.08-6.97 (m, 1H), 4.78(s, 1H), 4.66 (br s, 2H), 4.12-4.04 (m, 1H), 4.02-3.91 (m, 2H),3.37-3.30 (m, 1H), 3.22-3.13 (m, 1H), 2.12-1.85 (m, 3H), 1.46-1.32 (m,1H).

E238(S)-3-((3-fluorobenzyl)(methyl)amino)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E222 starting from(S)-3-((3-fluorobenzyl)amino)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2c]pyrimidin-1-one.

LC-MS (ESI): m/z 329 [M+H]⁺; 3.82 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.29-7.22 (m, 1H), 7.11-7.13 (m, 2H),6.91-6.85 (m, 1H), 4.59 (s, 1H), 4.37 (s, 2H), 4.12-4.07 (m, 1H),3.57-3.44 (m, 3H), 3.42 (s, 3H), 2.92-2.82 (m, 1H), 1.96-1.85 (m, 2H),1.75-1.71 (m, 1H), 1.56-1.35 (m, 3H).

E239(S)-3-((3,5-difluorobenzyl)(methyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E222 starting from(S)-3-((3,5-difluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-oneand iodomethane.

LC-MS (ESI): m/z 333 [M+H]⁺; 3.00 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 6.98-6.94 (m, 2H), 6.67-6.61 (m, 1H), 4.69(s, 1H), 4.34 (s, 2H), 4.11-4.06 (m, 1H), 3.98-3.84 (m, 2H), 3.41 (s,3H), 3.73-3.32 (m, 1H), 3.24-3.18 (m, 1H), 2.15-1.97 (m, 3H), 1.45-1.28(m, 1H).

E240(S)-3-((3,5-difluorobenzyl)(methyl)amino)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E222 starting from(S)-3-((3,5-difluorobenzyl)amino)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 347 [M+H]⁺; 3.17 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 6.98-6.94 (m, 2H), 6.66-6.60 (m, 1H), 4.54(s, 1H), 4.36 (s, 2H), 4.13-4.08 (m, 1H), 3.56-3.42 (m, 3H), 3.41 (s,3H), 2.91-2.84 (m, 1H), 1.96-1.89 (m, 2H), 1.76-1.72 (m, 1H), 1.59-1.37(m, 3H).

E241(R)-7-((2,4,5-trifluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E104 starting from (R)-7-chloro-3, 4, 11,11a-tetrahydropyrimido[6′,1′:2,3] imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (2,4,5-trifluorophenyl)methanamine.

LC-MS (ESI): m/z 353 [M+H]⁺; 3.07 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.37-7.28 (m, 1H), 7.18-7.10 (m, 1H), 5.03(s, 1H), 4.49-4.48 (m, 2H), 4.08-3.94 (m, 3H), 3.88-3.83 (m, 1H),3.60-3.48 (m, 3H), 3.41-3.31 (m, 2H).

E242(R)-7-((2,3-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E104 starting from (R)-7-chloro-3, 4, 11,11a-tetrahydropyrimido[6′,1′:2,3] imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (2,3-difluorophenyl)methanamine.

LC-MS (ESI): m/z 335 [M+H]⁺; 3.00 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.23-7.19 (m, 1H), 7.07-6.99 (m, 2H), 4.75(s, 1H), 4.72-4.59 (m, 2H), 4.06-3.85 (m, 4H), 3.57-3.43 (m, 2H),3.35-3.43 (m, 3H), 2.08-2.01 (m, 1H).

E243(S)-3-((2,4,5-trifluorobenzyl)amino)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E232 starting from (2,4,5-trifluorophenyl)methanamine and(S)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 351 [M+H]⁺; 3.54 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.31-7.28 (m, 1H), 6.93-6.84 (m, 1H), 4.63(s, 1H), 4.61-4.54 (m, 2H), 4.19-4.12 (m, 1H), 3.69-3.55 (m, 2H),3.50-3.44 (m, 1H), 2.97-2.90 (m, 1H), 1.97-1.88 (m, 2H), 1.71-1.65 (m,1H), 1.54-1.39 (m, 3H).

E244(S)-3-((2,3-difluorobenzyl)amino)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

To a solution of(S)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one(100 mg, 0.443 mmol) and (2,3-difluorophenyl)methanamine (95.0 mg, 0.665mmol) in NMP (1.5 mL) was added DIEA (572 mg, 4.43 mmol) at roomtemperature. The reaction mixture was stirred at 100° C. for 12 hours.The reaction cooled to room temperature, purified with prep-HPLC to givethe title compound (74 mg, 50%) as a off white solid.

LC-MS (ESI): m/z 333 [M+H]⁺; 3.48 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.22-7.17 (m, 1H), 7.07-7.01 (m, 2H),4.69-4.61 (m, 3H), 4.18-4.12 (m, 1H), 3.67-3.55 (m, 2H), 3.49-3.45 (m,1H), 2.96-2.92 (m, 1H), 1.96-1.89 (m, 2H), 1.67-1.66 (m, 1H), 1.53-1.38(m, 3H).

E245(S)-3-((2,3-difluorobenzyl)(methyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E222 starting from(S)-3-((2,3-difluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-oneand idodomethane.

LC-MS (ESI): m/z 333 [M+H]⁺; 3.01 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.39-7.35 (m, 1H), 7.06-7.00 (m, 2H), 4.79(s, 1H), 4.43 (s, 2H), 4.12-4.06 (m, 1H), 4.00-3.84 (m, 2H), 3.41 (s,3H), 3.38-3.34 (m, 1H), 3.27-3.18 (m, 1H), 2.15-2.08 (m, 2H), 2.06-1.96(m, 1H), 1.47-1.28 (m, 1H).

E246(R)-7-(3-fluorophenethoxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(R)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand 2-(3-fluorophenyl)ethanol.

LC-MS (ESI): m/z 332 [M+H]⁺; 3.48 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.28-7.21 (m, 1H), 7.02-6.91 (m, 3H), 4.93(s, 1H), 4.56 (t, 2H), 4.16-3.89 (m, 4H), 3.67-3.62 (m, 1H), 3.54-3.48(m, 1H), 3.40-3.33 (m, 2H), 3.01 (t, 2H).

E247(S)-3-(3-fluorophenethoxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(S)-3-chloro-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-oneand 2-(3-fluorophenyl)ethanol.

LC-MS (ESI): m/z 316 [M+H]⁺; 3.84 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.23-7.21 (m, 2H), 7.03-6.90 (m, 3H), 5.03(s, 1H), 4.58-4.53 (m, 2H), 4.15-4.00 (m, 3H), 3.39-3.35 (m, 1H),3.26-3.22 (m, 1H), 3.03-2.98 (m, 2H), 2.15-1.99 (m, 3H), 1.42 (t, 1H).

E248(S)-7-(3-fluorophenethoxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(S)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand 2-(3-fluorophenyl)ethanol.

LC-MS (ESI): m/z 332 [M+H]⁺; 3.47 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.26-7.23 (m, 1H), 7.02-6.90 (m, 3H), 4.93(s, 1H), 4.58 (t, 2H), 4.12-3.89 (m, 4H), 3.67-3.64 (m, 1H), 3.62-3.51(m, 1H), 3.40-3.33 (m, 3H), 3.01 (t, 2H).

E249(R)-3-(3-fluorophenethoxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(R)-3-chloro-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-oneand 2-(3-fluorophenyl)ethanol.

LC-MS (ESI): m/z 316 [M+H]⁺; 3.84 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.28-7.21 (m, 1H), 7.02-6.90 (m, 3H), 5.02(s, 1H), 4.55 (t, 2H), 4.15-4.00 (m, 3H), 3.39-3.34 (m, 1H), 3.28-3.22(m, 1H), 3.01 (t, 2H), 2.45-2.04 (m, 3H), 1.58-1.42 (m, 1H).

E250(S)-3-(methyl(2,4,5-trifluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E222 starting from(S)-3-((2,4,5-trifluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-oneand idodomethane.

LC-MS (ESI): m/z 351 [M+H]⁺; 3.09 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.54-7.45 (m, 1H), 6.92-6.83 (m, 1H), 4.74(s, 1H), 4.31 (s, 2H), 4.12-3.85 (m, 3H), 3.41 (s, 3H), 3.38-3.33 (m,1H), 3.27-3.18 (m, 1H), 2.17-1.99 (m, 3H), 1.45-1.37 (m, 1H).

E251(S)-3-(methyl(3,4,5-trifluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E222 starting from(S)-3-((3,4,5-trifluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-oneand idodomethane.

LC-MS (ESI): m/z 351 [M+H]⁺; 3.20 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.06 (t, 2H), 4.68 (s, 1H), 4.37 (s, 2H),4.16-3.87 (m, 3H), 3.50 (s, 3H), 3.46-3.35 (m, 1H), 3.25-3.15 (m, 1H),2.20-1.94 (m, 3H), 1.47-1.41 (m, 1H).

E252(S)-3-((3-fluorobenzyl)(methyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E232 starting from(S)-3-((3-fluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-oneand idodomethane.

LC-MS (ESI): m/z 315 [M+H]⁺; 2.94 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.24-7.22 (m, 1H), 7.21-7.13 (m, 2H),6.89-6.87 (m, 1H), 4.74 (s, 1H), 4.38 (s, 2H), 4.08-3.84 (m, 3H), 3.41(s, 3H), 3.40-3.31 (m, 1H), 3.21-3.17 (m, 1H), 2.21-1.94 (m, 3H),1.44-1.40 (m, 1H).

E253(S)-3-((2,4-difluorobenzyl)(methyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E232 starting from(S)-3-((2,4-difluorobenzyl)amino)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-oneand idodomethane.

LC-MS (ESI): m/z 333 [M+H]⁺; 3.00 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.62-7.53 (m, 1H), 6.88-6.73 (m, 2H), 4.78(s, 1H), 4.35 (s, 2H), 4.11-4.05 (m, 1H), 3.98-3.90 (m, 1H), 3.88-3.85(m, 1H), 3.40 (s, 3H), 3.37-3.33 (m, 1H), 3.26-3.17 (m, 1H), 2.16-1.93(m, 3H), 1.44-1.37 (m, 1H).

E254(R)-4-(2-((1-oxo-1,6,7,8,8a,9-hexahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)ethyl)benzonitrile

To a solution of(R)-3-(4-bromophenethoxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one(75 mg, 0.20 mmol) in DMF (4 mL) was added Zn(CN)₂ (47 mg, 0.40 mmol)and Pd(PPh₃)₄ (20 mg) under nitrogen. The reaction mixture was stirredat 150° C. for 20 min. The reaction mixture was concentrated. Theresidue was dissolved with water (40 mL), extracted with EtOAc (40mL×3). The combined organic layers were dried over anhydrous sodiumsulfate, filtered, concentrated under reduced pressure and purified byprep-HPLC to give the title compound (30 mg, yield 47%) as a whitesolid.

LC-MS (ESI): m/z 323 [M+H]⁺; 3.54 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.60-7.57 (m, 2H), 7.35 (d, 2H), 4.99 (s,1H), 4.60-4.55 (m, 2H), 4.15-4.00 (m, 3H), 3.39-3.35 (m, 1H), 3.28-3.21(m, 1H), 3.07 (d, 2H), 2.16-2.04 (m, 3H), 1.55-1.42 (m, 1H).

E255(S)-4-(2-((9-oxo-1,3,4,9,11,11a-hexahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-7-yl)oxy)ethyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E254 starting from(S)-7-(4-bromophenethoxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one.

LC-MS (ESI): m/z 339 [M+H]⁺; 3.19 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.58 (d, 2H), 7.35-7.26 (m, 2H), 4.90 (s,1H), 4.58 (t, 2H), 4.13-3.89 (m, 4H), 3.67-3.62 (m, 1H), 3.52-3.47 (m,1H), 3.41-3.32 (m, 3H), 3.09-3.05 (m, 2H).

E256(R)-7-(3-fluorophenethyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E224 starting from(R)-7-((3-fluorophenyl)ethynyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one.

LC-MS (ESI): m/z 316 [M+H]⁺; 3.05 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.26-7.21 (m, 1H), 7.00-6.88 (m, 3H), 5.29(s, 1H), 4.24-4.17 (m, 1H), 4.11-4.09 (m, 1H), 4.03-3.91 (m, 2H),3.75-3.69 (m, 1H), 3.49-3.35 (m, 4H), 3.04 (t, 2H), 2.76 (t, 2H).

E257(S)-7-(3-fluorophenethyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E224 starting from(R)-7-((3-fluorophenyl)ethynyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one.

LC-MS (ESI): m/z 316 [M+H]⁺; 3.06 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.26-7.21 (m, 1H), 7.00-6.88 (m, 3H), 5.29(s, 1H), 4.24-4.17 (m, 1H), 4.14-4.09 (m, 1H), 4.04-3.92 (m, 2H),3.76-3.72 (m, 1H), 3.53-3.36 (m, 4H), 3.04 (t, 2H), 2.77 (t, 2H).

E258(R)-7-((3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)benzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)phenyl)methanol and(R)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one.

LC-MS (ESI): m/z 438 [M+H]⁺; 4.03 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 6.94-6.90 (m, 2H), 5.32-5.25 (m, 2H), 5.01(s, 1H), 4.81 (t, 1H), 4.70 (t, 1H), 4.16-3.89 (m, 4H), 3.66-3.62 (m,1H), 3.54-3.48 (m, 1H), 3.40-3.33 (m, 3H), 2.16-2.07 (m, 2H), 1.06 (t,2H), 0.63 (t, 2H).

E259(S)-3-((3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)benzyl)oxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)phenyl)methanol and(S)-3-chloro-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one.

LC-MS (ESI): m/z 422 [M+H]+; 4.36 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 6.96-6.70 (m, 2H), 5.34-5.23 (m, 2H), 5.10(s, 1H), 4.84 (t, 1H), 4.68 (t, 1H), 4.16-4.00 (m, 3H), 3.43-3.36 (m,1H), 3.29-3.20 (m, 1H), 2.18-1.99 (m, 5H), 1.47-1.41 (m, 1H), 1.07 (t,2H), 0.66-0.62 (m, 2H).

E260(R)-7-((9-fluoro-3,4-dihydrospiro[benzo[b][1,4]dioxepine-2,1′-cyclopropan]-7-yl)methoxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

To a solution of(3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)phenyl)methanol (40 mg,0.16 mmol) and(R)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one(36 mg, 0.16 mmol) in DMF (4 mL) was added NaH (60% in mineral oil, 13mg, 0.33 mmol) at 0° C. The reaction mixture was stirred at roomtemperature for 2 hours. The reaction was quenched with water (1 mL) andextracted with EtOAc (5 mL×3). The separate organic solution wassuccessively washed with water (5 mL) and brine (5 mL). The extractswere combined and dried over Na₂SO₄, filtered, concentrated underreduced pressure and purified by prep-HPLC to give the title compound (9mg, 10%) as yellow oil.

LC-MS (ESI): m/z 416 [M+H]+; 2.89 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 6.82-6.79 (m, 2H), 5.26 (s, 2H), 5.05 (s,1H), 4.26-4.18 (m, 2H), 4.11-3.89 (m, 4H), 3.69-3.63 (m, 1H), 3.53-3.34(m, 4H), 2.20 (t, 2H), 1.06-1.03 (m, 2H), 0.61-0.57 (m, 2H).

E261(S)-3-((9-fluoro-3,4-dihydrospiro[benzo[b][1,4]dioxepine-2,1′-cyclopropan]-7-yl)methoxy)-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one

The title compound was prepared by a procedure similar to that describedfor E260 starting from(3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)phenyl)methanol and(S)-3-chloro-7,8,8a,9-tetrahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1(6H)-one.

LC-MS (ESI): m/z 400 [M+H]+; 2.58 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 6.83-6.80 (m, 2H), 5.32-5.21 (m, 2H), 5.11(s, 1H), 4.27-4.02 (m, 5H), 3.44-3.37 (m, 1H), 3.30-3.23 (m, 1H),2.26-1.98 (m, 5H), 1.47-1.42 (m, 1H), 1.08-1.04 (m, 2H), 0.62-0.58 (m,2H).

E262(S)-7-((3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)benzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)phenyl)methanol and(S)-7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one.

LC-MS (ESI): m/z 438 [M+H]+; 4.03 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.07 (d, 2H), 5.38 (s, 1H), 5.26 (s, 1H),4.80 (t, 1H), 4.64 (t, 1H), 4.15-4.12 9 (m, 2H), 4.02-3.96 (m, 1H),3.91-3.86 (m, 1H), 3.64-3.30 (m, 6H), 2.20-2.06 (m, 2H), 1.00-0.98 (m,2H), 0.70-0.65 (m, 2H).

E263(S)-3-((3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)benzyl)oxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)phenyl)methanol and(S)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 436 [M+H]+; 3.95 min (ret time).

¹H NMR (400 MHz, CDCl₃): δ 6.93 (d, J=8.4 Hz, 2H), 5.29 (s, 2H), 4.97(s, 1H), 4.85 (t, J=6.3 Hz, 1H), 4.69 (t, J=6.0 Hz, 1H), 4.23-4.16 (m,1H), 3.77-3.50 (m, 3H), 2.99-2.97 (m, 1H), 2.18-2.06 (m, 2H), 1.95-1.91(m, 1H), 1.82-1.73 (m, 2H), 1.53-1.45 (m, 3H), 1.07 (t, J=6.6 Hz, 2H),0.64 (t, J=6.6 Hz, 2H).

E264(S)-3-((9-fluoro-3,4-dihydrospiro[benzo[b][1,4]dioxepine-2,1′-cyclopropan]-7-yl)methoxy)-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one

The title compound was prepared by a procedure similar to that describedfor E63 starting from(3,5-difluoro-4-(1-(2-fluoroethyl)cyclopropoxy)phenyl)methanol and(S)-3-chloro-6,7,8,9,9a,10-hexahydro-1H-pyrido[1′,2′:3,4]imidazo[1,2-c]pyrimidin-1-one.

LC-MS (ESI): m/z 414 [M+H]+; 4.02 min (ret time).

¹H NMR (400 MHz, CDCl₃): δ 6.83-6.79 (m, 2H), 5.26 (s, 2H), 4.97 (s,1H), 4.26-4.17 (m, 3H), 3.77-3.48 (m, 3H), 3.01-2.97 (m, 1H), 2.21-2.17(m, 2H), 1.96-1.91 (m, 2H), 1.76-1.72 (m, 1H), 1.54-1.44 (m, 3H),1.07-1.03 (m, 2H), 0.61-0.57 (m, 2H).

E265(S)-7-(2,4-difluorophenethyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E224 starting from(S)-7-((2,4-difluorophenyl)ethynyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one.

LC-MS (ESI): m/z 334 [M+H]+; 2.60 min (ret time).

¹H NMR (300 MHz, CDCl₃): δ 7.20-7.14 (m, 1H), 6.79-6.73 (m, 2H), 5.31(s, 1H), 4.26-4.17 (m, 1H), 4.11-4.03 (m, 1H), 4.00-3.92 (m, 2H),3.74-3.68 (m, 1H), 3.52-3.46 (m, 1H), 3.44-3.34 (m, 3H), 3.05-3.00 (m,2H), 2.77-2.71 (m, 2H).

E2662-Fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile

To a solution of tert-Butyl7-chloro-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2(9H)-carboxylate (2.95 g, 9.03 mmol) and2-fluoro-5-(hydroxymethyl)benzonitrile (1.364 g, 9.03 mmol) in 2-MeTHF(64 mL) was added NaH (0.910 g, 22.75 mmol) in small portions. Thereaction was stirred at room temperature for 35 min then quenched withsaturated NH₄Cl. The layers were separated, and the aqueous layer wasextracted with EtOAc for 3 times. The combined organics were then washedwith brine, dried (anhydrous Na₂SO₄), filtered and concentrated. Thecrude was purified on a Combiflash silica cartridge (80 g) (0-15%MeOH/DCM) to give the intermediate tert-butyl7-((3-cyano-4-fluorobenzyl)oxy)-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2(9H)-carboxylate(3.44 g, 7.79 mmol, 86% yield) as a pale yellow brittle solid. (LC/MS:m/z 442.2 (M+H)⁺, 0.82 min (ret. time)). To this intermediate (3.44 g,7.79 mmol) dissolved in DCM (18 mL) was added TFA (18 mL, 234 mmol). Thereaction was stirred for 0.75 h at room temperature and the mixture wasdiluted with DCM (50 mL) and concentrated. The crude material wasredissolved in MeOH/DCM and concentrated under reduced pressure (threetimes), then dissolved in THF and concentrated under reduced pressure(three times) resulting in the title compound (4.42 g, 7.76 mmol, 100%yield) as a tan brittle solid.

LC/MS: m/z 341.9 (M+H)⁺, 0.54 min (ret. time).

¹H NMR (300 MHz, CD₃OD): δ 7.82-7.68 (m, 2H), 7.30 (t, J=8.78 Hz, 1H),5.44-5.30 (m, 2H), 5.20 (s, 1H), 4.16 (dd, J=11.42, 9.16 Hz, 1H),4.05-3.89 (m, 1H), 3.71-3.48 (m, 2H), 3.29-3.10 (m, 2H), 3.01 (dd,J=12.55, 2.76 Hz, 1H), 2.83-2.57 (m, 2H).

The following compounds E267-E279 were prepared by a procedure similarto that described for E266 starting from the requisitechloropyrimidinone intermediate and the requisite benzyl alcohol:

TABLE 2 Ret. time Ex # Name Structure (min) m/z ¹H NMR (400 MHz) E2677-((3-Fluoro- 4-((2-(trifluoro- methyl)pyridin- 4-yl)oxy)- benzyl)oxy)-3,4,11,11a- tetrahydro-1H- pyrazino- [1′,2′:3,4]- imidazo[1,2-c]pyrimidin- 9(2H)-one

0.73 478.1 (CHLOROFORM-d) δ ppm 1.84 (br. s., 1 H) 2.69 (t, J = 11.17Hz, 1 H) 2.80 (td, J = 11.86, 3.14 Hz, 1 H) 3.04 (d, J = 10.54 Hz, 1 H)3.15-3.29 (m, 2 H) 3.45 (d, J = 11.54 Hz, 1 H) 3.70 (dd, J = 11.54, 6.53Hz, 1 H) 3.87-4.02 (m, 1 H) 4.19 (dd, J = 11.42, 9.16 Hz, 1 H) 5.03 (s,1 H) 5.44 (s, 2 H) 6.96 (dd, J = 5.40, 1.63 Hz, 1 H) 7.15-7.37 (m, 4 H)8.58 (d, J = 5.52 Hz, 1 H) E268 7-((2,3-Di- fluorobenzyl)- oxy)-3,4,11,11a-tetrahydro- 1H-pyrazino- [1′,2′:3,4]- imidazo[1,2- c]pyrimidin-9(2H)-one

0.52 335.3 (CHLOROFORM-d) δ ppm 1.79 (br. s., 1 H) 2.64- 2.85 (m, 2 H)3.03 (dd, J = 12.05, 2.51 Hz, 1 H) 3.13-3.29 (m, 2 H) 3.43 (dd, J =13.05, 2.51 Hz, 1 H) 3.70 (dd, J = 11.54, 6.53 Hz, 1 H) 3.88-3.99 (m, 1H) 4.19 (dd, J = 11.42, 8.91 Hz, 1 H) 5.00 (s, 1 H) 5.49 (s, 2 H)7.03-7.20 (m, 2 H) 7.24 (t, J = 6.65 Hz, 1 H) E269 5-(((11,11-Dideutero-9- oxo-2,3,4,9, 11,11a-hexa- hydro-1H- pyrazino- [1′,2′:3,4]-imidazo- [1,2-c]- pyrimidin- 7-yl)oxy)- methyl)-2- fluorobenzo- nitrile2,2,2-

0.54 344.1 (METHANOL-d₄) δ ppm 2.66 (s, 2 H) 3.21-3.36 (m, 2 H)3.53-3.77 (m, 3 H) 4.25 (d, J = 12.05 Hz, 1 H) 4.56 (d, J = 9.03 Hz, 1H) 5.41 (s, 2 H) 5.92 (s, 1 H) 7.44 (t, J = 8.91 Hz, 1 H) 7.80-7.87 (m,1 H) 7.90 (d, J = 6.02 Hz, 1 H) trifluoroacetate E270 7-((3,5-Difluoro-4- ((2-(trifluoro- methyl)- pyridin-4-yl)- oxy)benzyl)-oxy)-3,4,11, 11a-tetrahydro- 1H-pyrazino- [1′,2′:3,4]- imidazo- [1,2-c]-pyrimidin- 9(2H)-one

0.76 496.1 (CHLOROFORM-d) δ ppm 2.08 (br. s., 1 H) 2.62- 2.88 (m, 2 H)3.06 (d, J = 11.80 Hz, 1 H) 3.15-3.32 (m, 2H) 3.46 (d, J = 12.80 Hz, 1H) 3.70 (dd, J = 11.04, 6.53 Hz, 1 H) 3.97 (m, 1 H) 4.13-4.27 (m, 1 H)5.05 (s, 1 H) 5.34- 5.51 (m, 2 H) 6.95-7.03 (m, 1 H) 7.13 (d, J = 8.78Hz, 2 H) 7.23-7.31 (m, 1 H) 8.60 (m, 1 H) E271 2-Methyl-5- (((9-oxo-2,3,4,9,11,11a- hexahydro- 1H-pyrazino- [1′,2′:3,4]- imidazo[1,2-c]pyrimidin- 7-yl)oxy)- methyl)- benzonitrile

0.53 338.0 (CHLOROFORM-d) δ ppm 1.79 (br. s., 1 H) 2.56 (s, 3 H) 2.70(t, J = 11.17 Hz, 1 H) 2.75-2.87 (m, 1 H) 3.05 (d, J = 11.80 Hz, 1 H)3.13-3.32 (m, 2H) 3.46 (d, J = 11 Hz, 1 H) 3.71 (dd, J = 11.54, 6.53 Hz,1 H) 3.87-4.02 (m, 1 H) 4.19 (dd, J = 11.42, 9.16 Hz, 1 H) 5.02 (s, 1 H)5.32- 5.46 (m, 2 H) 7.25-7.37 (m, 1 H) 7.52 (d, J = 7.78 Hz, 1 H) 7.66(s, 1 H) E272 3-(((9-Oxo- 2,3,4,9,11, 11a-hexa- hydro-1H- pyrazino-[1′,2′:3,4]- imidazo[1,2- c]pyrimidin- 7-yl)oxy)- methyl)benzo- nitrile

0.52 324.4 (CHLOROFORM-d) δ ppm 1.81 (br. s., 1 H) 2.58- 2.86 (m, 2 H)2.98-3.32 (m, 3 H) 3.45 (d, J = 12.30 Hz, 1 H) 3.69 (dd, J = 11.54, 6.53Hz, 1 H) 3.85- 4.02 (m, 1 H) 4.18 (dd, J = 11.17, 9.16 Hz, 1 H) 5.03 (s,1 H) 5.34-5.53 (m, 2 H) 7.39-7.74 (m, 4H) E273 7-((3,5- Difluoro-4-((5-(trifluoro- methyl)- pyridin-3-yl)- oxy)benzyl)- oxy)-3,4,11,11a-tetrahydro- 1H-pyrazino- [1′,2′:3,4]- imidazo[1,2- c]pyrimidin-9(2H)-one

0.74 496.3 (CHLOROFORM-d) δ ppm 1.79 (br. s., 1 H) 2.62-2.87 (m, 2 H)3.04 (d, J = 11.29 Hz, 1 H) 3.11-3.30 (m, 2 H) 3.44 (d, J = 11.80 Hz, 1H) 3.69 (dd, J = 11.54, 6.53 Hz, 1 H) 3.86- 3.99 (m, 1 H) 4.18 (dd, J =11.17, 9.41 Hz, 1 H) 5.03 (s, 1 H) 5.32-5.52 (m, 2H) 7.11 (d, J = 8.53Hz, 2 H) 7.40 (br. s., 1 H) 8.45-8.70 (m, 2 H) E274 7-((3,4- Difluoro-benzyl)oxy)- 3,4,11,11a- tetrahydro- 1H-pyrazino- [1′,2′:3,4]-imidazo[1,2- c]pyrimidin- 9(2H)-one

0.52 334.9 (METHANOL-d₄) δ ppm 2.62-2.85 (m, 2 H) 3.02 (d, J = 12.80 Hz,1 H) 3.13-3.31 (m, 2 H) 3.59- 3.75 (m, 2 H) 3.93-4.08 (m, 1 H) 4.13-4.28(m, 1 H) 5.25-5.42 (m, 3 H) 7.21-7.33 (m, 2 H) 7.33- 7.46 (m, 1H) E2757-((3-Bromo- 4-chloro- benzyl)oxy)- 3,4,11,11a- tetrahydro- 1H-pyrazino-[1′,2′:3,4]- imidiazo[1,2- c]pyrimidin- 9(2H)-one

0.69 411.0 (CHLOROFORM-d) δ ppm 2.05 (s, 1 H) 2.62-2.86 (m, 2 H) 3.04(d, J = 11.04 Hz, 1 H) 3.13-3.30 (m, 2 H) 3.43 (d, J = 13.05 Hz, 1 H)3.69 (dd, J = 11.54, 6.53 Hz, 1 H) 3.89-4.02 (m, 1 H) 4.18 (dd, J =10.92, 9.41 Hz, 1 H) 5.00 (s, 1 H) 5.28-5.42 (m, 2 H) 7.29 (d, J = 8.03Hz, 1 H) 7.42 (d, J = 8.28 Hz, 1 H) 7.67 (s, 1 H) E276 7-((3-Bromo-4-fluoro- benzyl)oxy)- 3,4,11,11a- tetrahydro- 1H-pyrazino- [1′,2′:3,4]-imidazo[1,2- c]pyrimidin- 9(2H)-one

0.59 394.9 (CHLOROFORM-d) δ ppm 1.83 (br, s., 1 H) 2.69 (t, J = 11.29Hz, 1 H) 2.79 (td, J = 11.92, 3.01 Hz, 1 H) 3.04 (d, J = 11.80 Hz, 1 H)3.11-3.31 (m, 2 H) 3.43 (d, J = 12.55 Hz, 1 H) 3.69 (dd, J = 11.67, 6.40Hz, 1 H) 3.84- 4.02 (m, 1 H) 4.18 (dd, J = 11.17, 9.16 Hz, 1 H) 4.99 (s,1 H) 5.17-5.48 (m, 2 H) 7.11 (t, J = 8.41 Hz, 1 H) 7.21-7.48 (m, 1 H)7.62 (d, J = 6.27 Hz, 1 H) E277 7-((3-Chloro- 4-fluoro- benzyl)oxy)-3,4,11,11a- tetrahydro- 1H-pyrazino- [1′,2′:3,4]- imidazo[1,2-c]pyrimidin- 9(2H)-one

0.61 351.3 (CHLOROFORM-d) δ ppm 2.57 (br. s., 1 H) 2.71 (t, J = 11.29Hz, 1 H) 2.81 (td, J = 12.05, 3.26 Hz, 1 H) 3.06 (d, J = 12.05 Hz, 1 H)3.15-3.32 (m, 2 H) 3.44 (d, J = 13.05 Hz, 1 H) 3.69 (dd, J = 11.67, 6.40Hz, 1 H) 3.91- 4.04 (m, 1 H) 4.18 (dd, J = 11.29, 9.29 Hz, 1 H) 5.00 (s,1 H) 5.28-5.41 (m, 2H) 7.13 (t, J = 8.66 Hz, 1 H) 7.24-7.33 (m, 1 H)7.47 (d, J = 7.03 Hz, 1 H) E278 2-Methoxy- 5-(((9-oxo- 2,3,4,9,11,11a-hexa- hydro-1H- pyrazino- [1′,2′:3,4]- imidazo[1,2- c]pyrimidin-7-yl)oxy)- methyl)benzo- nitrile

0.52 354.0 (CHLOROFORM-d) δ ppm 1.84 (br. s., 1 H) 2.68 (t, J = 11.17Hz, 1 H) 2.78 (td, J = 11.98, 2.89 Hz, 1 H) 3.02 (d, J = 11.80 Hz, 1 H)3.12-3.28 (m, 2 H) 3.42 (d, J = 11.54 Hz, 1 H) 3.67 (dd, J = 11.67, 6.40Hz, 1 H) 3.86-3.96 (m, 4 H) 4.05- 4.25 (m, 1 H) 4.96 (s, 1 H) 5.25-5.40(m, 2 H) 6.94 (J = 8.53 Hz, 1 H) 7.54-7.65 (m, 2 H) E279 7-((3,5-Difluoro-4- ((6-methyl- pyridin-3-yl)- oxy)benzyl)- oxy)-3,4,11,11a-tetrahydro- 1H-pyrazino- [1′,2′:3,4]- imidazo[1,2- c]pyrimidin-9(2H)-one

0.53 442.0 (CHLOROFORM-d) δ ppm 1.15 (s, 1 H) 2.40 (s, 3 H) 2.57 (t, J =11.54 Hz, 1 H) 2.67 (td, J = 12.17, 3.51 Hz, 1 H) 2.94 (dd, J = 12.42,2.38 Hz, 1 H) 3.03-3.21 (m, 2 H) 3.38 (dd, J = 13.18, 2.64 Hz, 1 H) 3.55(dd, J = 11.54, 6.78 Hz, 1 H) 3.81-3.91 (m, 1 H) 4.07 (dd, J = 11.42,9.16 Hz, 1 H) 4.99 (s, 1 H) 5.17-5.29 (m, 2 H) 6.95-7.11 (m, 4 H) 8.08(d, J = 2.76 Hz, 1 H)

E280

Method A

5-(((2-Ethyl-9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)-2-fluorobenzonitrile

To a solution of2-fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile(43 mg, 0.126 mmol) in DCM (0.4 mL) at 0° C. was added TEA (0.04 mL,0.287 mmol) and bromoethane (0.02 mL, 0.27 mmol). The reaction was thenwarmed to room temperature and stirred for 92 hrs. The mixture wasconcentrated under a stream of nitrogen at 50° C., taken up in DCM,applied to isolute, and concentrated under a stream of nitrogen at 50°C. The crude product was purified on a Combiflash silica cartridge (4 g)[0-20% MeOH (1% NH₄OH)/DCM] then by prep reverse phase HPLC [0-50%CH₃CN/H₂O (0.1% NH₄OH)] to give the title compound E280 (22 mg, 0.060mmol, 47.3% yield) as an amorphous white solid.

LC/MS: m/z 370.0 (M+H)⁺, 0.55 min (ret. time).

¹H NMR (400 MHz, CDCl₃): δ 1.09 (t, J=7.03 Hz, 3H) 2.01 (t, J=11.04 Hz,1H) 2.12 (td, J=11.67, 3.01 Hz, 1H) 2.49 (q, J=7 Hz, 2H) 2.87 (d,J=11.29 Hz, 1H) 3.00 (d, J=11.04 Hz, 1H) 3.24-3.39 (m, 1H) 3.40-3.55 (m,1H) 3.73 (dd, J=11.54, 5.77 Hz, 1H) 3.93-4.08 (m, 1H) 4.10-4.26 (m, 1H)4.99 (s, 1H) 5.31-5.47 (m, 2H) 7.19 (t, J=8.53 Hz, 1H) 7.56-7.71 (m,2H).

E281

Method B

5-(((2-Acetyl-9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)-2-fluorobenzonitrile,Trifluoroacetic Acid Salt

To a solution of2-fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile(80 mg, 0.141 mmol) in DCM (1.3 mL) was added DIPEA (0.1 mL, 0.573mmol), followed by acetyl chloride (0.01 mL, 0.140 mmol) in one portionat room temperature. The reaction was stirred for 45 min, diluted withDCM (2 mL), and washed with saturated NH₄Cl (1 mL×3), brine (1 mL),dried over anhydrous sodium sulfate, filtered and concentrated. Thecrude was purified on a Combiflash silica cartridge (4 g) (0-15%MeOH/DCM) then by prep reverse phase HPLC [10-90% CH₃CN/H₂O (0.1% TFA)]to give the title compound E281 (31 mg, 0.062 mmol, 44.4% yield) as anamorphous white solid.

LC/MS: m/z 384.0 (M+H)⁺, 0.61 min (ret. time).

¹H NMR (400 MHz, CD₃OD): δ 2.15-2.23 (s, 3H) 2.69-2.89 (m, 1H) 3.22-3.46(m, 2H) 3.79-4.39 (m, 5H) 4.70-4.93 (m, 1H) 5.33-5.45 (m, 3H) 7.38 (t,J=8.78 Hz, 1H) 7.75-7.88 (m, 2H)

E282

Method C

tert-Butyl(2-(7-((3-cyano-4-fluorobenzyl)oxy)-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-2(9H)-yl)-2-oxoethyl)carbamate

A solution of tert-butyl7-((3-cyano-4-fluorobenzyl)oxy)-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2(9H)-carboxylate(81 mg, 0.183 mmol) and HCl (3M in CPME) (2.5 mL, 7.50 mmol) was stirredat room temperature for 3 hrs and then concentrated resulting in a tanpowder. The powder was suspended in EtOAc (3 mL) and cooled to 0° C.,TEA (0.3 mL, 2.152 mmol) was then added, followed by2-((tert-butoxycarbonyl)amino)acetic acid (38 mg, 0.217 mmol) and T3P(50 wt % in EtOAc) (175 mg, 0.275 mmol). The resulting mixture wasstirred a further 1.5 hrs and then concentrated. The crude product waspurified on a Combiflash silica cartridge (12 g) (0-15% MeOH/DCM) togive the intermediate tert-butyl(2-(7-((3-cyano-4-fluorobenzyl)oxy)-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-2(9H)-yl)-2-oxoethyl)carbamate(130 mg, 0.227 mmol, 124% yield) as an amorphous white solid. (LC/MS:m/z 499.2 (M+H)⁺, 0.75 min (ret. time)). To this intermediate (130 mg,0.261 mmol) was added HCl (3M in CPME) (3.5 mL, 10.50 mmol) and thereaction was stirred for 1 hr. The mixture was then concentrated and thecrude was dissolved in DMSO:H₂O (2.1 mL), filtered through a 0.45 μmacrodisc, and purified by prep reverse phase HPLC [10-90% CH₃CN/H₂O(0.1% NH₄OH)] to give the title compound (11 mg, 0.028 mmol, 10.59%yield) as an amorphous white solid.

LC/MS: m/z 399.0 (M+H)⁺, 0.49 min (ret. time).

¹H NMR (400 MHz, CD₃OD): δ 2.75 (m., 1H) 3.10-3.29 (m, 2H) 3.64-4.13 (m,6H) 4.14-4.26 (m, 1H) 4.56-4.77 (m, 1H) 5.24-5.45 (m, 4H) 7.30 (t,J=8.91 Hz, 1H) 7.70-7.82 (m, 2H)

E283

Method D

5-(((2-(Ethylsulfonyl)-9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)-2-fluorobenzonitrile

To a solution of2-fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrilein DCM (1.373 mL) was added first DIPEA (0.1 mL, 0.573 mmol), followedby ethanesulfonyl chloride (0.02 mL, 0.179 mmol) in one portion at roomtemperature. The reaction was stirred for 1 h, diluted with DCM (2 mL),and washed with saturated NH₄Cl (1 mL, three times), brine (1 mL), driedover anhydrous sodium sulfate, filtered, and concentrated. The crude waspurified by prep reverse phase HPLC [10-90% CH₃CN/H₂O (0.1% TFA)] thenpurified on a Combiflash silica cartridge (12 g) [0-10% (1%NH₄OH/MeOH)/DCM] to give the title compound (25 mg, 0.058 mmol, 38.6%yield) as an amorphous white solid.

LC/MS: m/z 434.1 (M+H)⁺, 0.68 min (ret. time).

¹H NMR (400 MHz, CD₃OD, CD₂Cl₂) δ ppm 1.35 (t, J=7.40 Hz, 3H) 2.82-3.11(m, 4H) 3.28-3.40 (m, 1H) 3.62-3.75 (m, 2H) 3.81 (dd, J=12.55, 1.51 Hz,1H) 3.97 (dt, J=12.30, 1.76 Hz, 1H) 4.03-4.14 (m, 1H) 4.14-4.25 (m, 1H)5.29-5.42 (m, 3H) 7.29 (t, J=8.78 Hz, 1H) 7.68-7.79 (m, 2H)

E284

Method E

5-(((2-(2-(Dimethylamino)acetyl)-9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)-2-fluorobenzonitrile

To a solution of E266 (44 mg, 0.129 mmol) and 2-(dimethylamino)aceticacid (17 mg, 0.165 mmol) in dichloromethane (DCM) (1 mL) at roomtemperature was added first DIPEA (0.03 mL, 0.172 mmol), followed by T3P(50 wt. % in EtOAc) (0.09 mL, 0.151 mmol). The reaction was stirred for1 h at room temperature then diluted with DCM (3 mL), washed withsaturated NaHCO₃ (2 mL, two times), brine (2 mL), dried over anhydroussodium sulfate, filtered and concentrated. The crude product waspurified on a Combiflash silica cartridge (12 g) [0-10% (1%NH₄OH/MeOH)/DCM] then by prep reverse phase HPLC [10-90% CH₃CN/H₂O (0.1%NH₄OH)] to give the title compound (16 mg, 0.038 mmol, 29.1% yield) asan amorphous white solid.

LC/MS: m/z 427.3 (M+H)⁺, 0.51 min (ret. time).

¹H NMR (400 MHz, CD₃OD): δ ppm 2.31 (s, 6H) 2.68-2.85 (m, 1H) 3.13-3.26(m, 4H) 3.70-3.79 (m, 2H) 3.94-4.33 (m, 3H) 4.53-4.76 (m, 1H) 5.38 (m,3H) 7.33-7.41 (m, 1H) 7.76-7.89 (m, 2H)

The following compounds E285-E308 listed in Table 3 were prepared by aprocedure similar to that described for E280-E284 starting from therequisite fused piperazine and the requisite electrophile:

TABLE 3 LC/MS ret. Method Time Ex # Name Structure Used (min MS ¹H NMR(400 MHz) E285 5-(((2- Acetyl-11, 11-di- deutero-9- oxo-2,3, 4,9,11,11a-hexa- hydro-1H- pyrazino- [1′,2′:3,4]- imidazo- [1,2-c]- pyrimidin-7-yl)oxy)-

B 0.57 386.0 (CD₃OD) δ ppm 2.11 (s, 3 H) 2.53-2.76 (m, 1 H) 3.06-3.31(m, 2 H) 3.55- 3.67 (m, 1 H) 3.89 (d, J = 10.04 Hz, 1 H) 3.94-4.11 (m, 1H) 4.53-4.77 (m, 1 H) 5.18- 5.38 (m, 3 H) 7.25 (t, J = 8.78 Hz, 1H)7.65- methyl)-2- 7.77 (m, 2 H) fluoroben- zonitrile E286 2-Fluoro-5-(((2- (methyl- sulfonyl)- 9-oxo-2,3, 4,9,11,11a- hexahydro- 1H-pyrazino- [1′,2′:3,4]- imidazo- [1,2-c]- pyrimidin-

D 0.62 420.1 (CDCl₃) δ ppm 2.75 (t, J = 11.29 Hz, 1 H) 2.83-2.94 (m, 4H) 3.35-3.49 (m, 1 H) 3.60 (d, J = 12.80 Hz, 1 H) 3.78 (dd, J = 11.80,5.52 Hz, 1 H) 3.87 (d, J = 12.30 Hz, 1 H) 3.98 (d, J = 10.54 Hz, 1 H)4.12 (br. s., 1 H) 4.20-4.28 (m, 7-yl)oxy)- 1 H) 5.06 (s, 1 H) methyl)-5.33-5.50 (m, benzoni- 2 H) 7.21 (t, J = trilehydro- 8.66 Hz, 1 H)chloride 7.60-7.71 (m, 2 H) E287 5-(((11, 11-Di- deutero-2- (methyl-sulfonyl)- 9-oxo-2,3, 4,9,11, 11a-hexa- hydro-1H- pyrazino- [1′,2′:3,4]-imidazo- [1,2-c]- pyrimidin-

D 0.64 422.0 (CD₃OD) δ ppm 2.78-2.94 (m, 5 H) 3.36-3.41 (m, 1 H) 3.78(br. s., 2 H) 3.91-3.99 (m, 1 H) 4.08-4.18 (m, 1 H) 5.27- 5.39 (m, 3 H)7.31 (s, 1 H) 7.80 (d, J = 6.53 Hz, 2 H) 7-yl)oxy)- methyl)-2-fluoroben- zonitrile E288 5-(((2-(3- Amino- propan- oyl)-9- oxo-2,3,4,9,11,11a- hexahydro- 1H-pyra- zino[1′,2′: 3,4]imi- dazo[1,2- c]pyrimi-din-7-yl)-

C 0.49 413.1 (CD₃OD) δ ppm 2.68-2.90 (m, 3 H) 3.08-3.33 (m, 4 H)3.72-3.84 (m, 2 H) 3.97-4.29 (m, 3 H) 4.60-4.84 (m, 1 H) 5.34-5.45 (m, 3H) 7.40 (t, J = 8.91 Hz, 1 H) 7.80-7.86 (m, 1 H) 7.89 (d, J = 5.77 Hz, 1H) oxy)meth- yl)-2- fluoroben- zonitrile E289 2-Fluoro- 5-(((9- oxo-2-propionyl- 2,3,4,9,11, 11a-hexa- hydro-1H- pyrazino- [1′,2′:3,4]-imidazo- [1,2-c]- pyrimidin- 7-yl)oxy)-

B 0.57 398.1 (CD₃OD) δ ppm 1.17 (t, J = 7.40 Hz, 3 H) 2.53 (m, 2 H) 2.68(s, 1 H) 2.86 (d, J = 11.80 Hz, 1 H) 3.35- 3.55 (m, 1 H) 3.82-3.94 (m, 1H) 4.09 (d, J = 13.05 Hz, 1 H) 4.14-4.45 (m, 3 H) 4.72-4.92 (m, 2 H)5.43 (s, methyl)- 2 H) 7.48 (t, J = benzo- 8.78 Hz, 1 H) nitrile7.83-7.91 (m, 2,2,2- 1 H) 7.94 (d, J = trifluoro- 5.77 Hz, 1 H) acetateE290 2-Fluoro- 5-(((2- isobutyryl- 9-oxo- 2,3,4,9,11, 11a-hexa-hydro-1H- pyrazino- [1′,2′:3,4]- imidazo- [1,2-c]- pyrimidin- 7-yl)oxy)-

B 0.67 412.2 (CD₃OD) δ ppm 1.17 (br. s., 6 H) 2.87 (m, 1 H) 3.04 (dt, J= 13.30, 6.65 Hz, 1 H) 3.37-3.53 (m, 2 H) 3.90 (dd, J = 10.92, 7.15 Hz,1 H) 4.12 (d, J = 11.29 Hz, 1 H) 4.18-4.52 (m, 3 H) 4.69-4.96 methyl)-(m, 2 H) 5.43 (s, benzo- 2 H) 7.48 (t, J = nitrile 8.91 Hz, 1 H)2,2,2-tri- 7.76-8.02 (m, fluoro- 2 H) acetate E291 5-(((2- Butyryl-9-oxo-2,3, 4,9,11, 11a-hexa- hydro-1H- pyrazino- [1′,2′:3,4]- imidazo-[1,2-c]- pyrimidin-

B 0.68 412.3 (CD₃OD) δ ppm 0.92 (t, J = 7.40 Hz, 3 H) 1.47- 1.70 (m, 2H) 2.40 (t, J = 7.15 Hz, 2 H) 2.69-2.86 (m, 1 H) 3.26-3.46 (m, 2 H)3.73-3.86 (m, 1 H) 4.01 (d, J = 13.05 Hz, 1 H) 4.12 (d, J = 12.557-yl)oxy)- Hz, 1 H) 4.19-4.37 methyl)-2- (m, 2 H) 4.60-4.85 fluoro- (m,2 H) 5.34 (s, benzo- 2 H) 7.39 (t, J = nitrile 8.91 Hz, 1 H) 771- 2,2,2-7.93 (m, 2 H) trifluoro- acetate E292 5-(((2- (cyclo- propane-carbonyl)- 9-oxo- 2,3,4,9,11, 11a-hexa- hydro-1H- pyrazino- [1′,2′:3,4]-imidazo-

B 0.67 410.1 (CD₃OD) δ ppm 0.75-0.97 (m, 4 H) 1.97 (m, 1 H) 2.60 (s, 1H) 2.84 (br. s., 1 H) 3.35 (br. s., 2 H) 3.82 (br. s., 1 H) 3.92-4.36(m, 3 H) 4.41- 4.84 (m, 2 H) 5.35 (s, 2 H) 7.40 (t, J = 8.91 Hz,[1,2-c]- 1 H) 7.73-7.96 pyrimidin- (m, 2 H) 7-yl)oxy)- methyl)-2-fluoro- benzo- nitrile 2,2,2- trifluoro- acetate E293 2-Fluoro-5-(((2-(3- methyl- butanoyl)- 9-oxo- 2,3,4,9,11, 11a-hexa- hydro-1Hpyrazino [1′,2′:3,4]- imidazo- [1,2-c]- pyrimidin-

B 0.75 426.1 (CD₃OD) δ ppm 1.02 (d, J = 6.3 Hz, 6 H) 2.12 (sept, J = 6.3Hz, 1 H) 2.31-2.46 (m, 2 H) 2.79- 2.94 (m, 1 H) 3.30-3.53 (m, 2 H)3.84-3.95 (m, 1 H) 4.10 (d, J = 13.05 Hz, 1 H) 4.23 (d, J = 11.29 Hz, 1H) 7-yl)oxy)- 4.27-4.46 (m, methyl)- 2 H) 4.73-4.94 benzo- (m, 2 H) 5.43nitrile (s, 2 H) 7.48 (t, J = 8.91 Hz, 1 H) 7.83-7.98 (m, 2 H) E2942-Fluoro- 5-(((9- oxo-2- pivaloyl- 2,3,4,9,11, 11a-hexa- hydro-1H-pyrazino- [1′,2′:3,4]- imidazo- [1,2-c]-

B 0.74 426.0 (CD₃OD) δ ppm 1.33 (s, 9 H) 2.95- 3.16 (m, 2 H) 3.33-3.42(m, 1 H) 3.85 (dd, J = 11.80, 7.28 Hz, 1 H) 3.96 (br. d, J = 13.30 Hz, 1H) 4.11-4.27 (m, 1 H) 4.28- 4.39 (m, 1 H) pyrimidin- 4.59 (br. d, J =7-yl)oxy)- 13.55 Hz, 1 H) methyl)- 4.72-4.79 (m, benzo- 2 H) 5.40 (s,nitrile 2 H) 7.41 (t, J = 2,2,2- 8.91 Hz, 1 H) trifluoro- 7.76-7.92 (m,acetate 2 H) E295 2-Fluoro- 5-(((2- (isoprop- ylsul- fonyl)-9-oxo-2,3,4, 9,11,11a, hexahydro- 1H- pyrazino- [1′,2′:3,4]-

D 0.71 448.2 (CD₃OD) δ ppm 1.37 (d, J = 6.78 Hz, 6 H) 3.11- 3.27 (m, 2H) 3.35-3.44 (m, 1 H) 3.44-3.56 (m, 1 H) 3.85 (m, 1 H) 3.90-4.02 (m, 1H) 4.02- 4.20 (m, 2 H) 4.27-4.44 (m, imidazo- 2 H) 5.42 (s, [1,2-c]- 2H) 7.48 (t, pyrimidin- J = 8.78 Hz, 7-yl)oxy) 1 H) 7.87 (td, methyl)- J= 5.52, 2.51 benzo- Hz, 1 H) 7.94 nitrile (d, J = 6.02 Hz, 2,2,2- 1 H)trifluoro- acetate E296 5-(((2- (Cyclo- propyl- sulfonyl- 9-oxo-2,3,4,9, 11,11a- hexa- hydro-1H- pyrazino- [1′,2′:3,4]-

D 0.7 446.1 (CD₃OD) δ ppm 1.00-1.19 (m, 4 H) 2.50-2.63 (m, 1H) 3.06-3.20(m, 2H) 3.52 (td, J = 12.80, 3.51 Hz, 1 H) 3.84-3.97 (m, 2 H) 4.11 (d, J= 13.30 Hz, 2 H) 4.32-4.45 (m, 2H) 5.36-5.48 imidazo- (m, 2H) 5.96 (s,[1,2-c]- 1H) 7.47 (t, J = pyrimidin- 8.91 Hz, 1 H) 7-yl)oxy)- 7.83-7.90(m, methyl)-2- 1 H) 7.93 (d, J = fluoro- 6.02 Hz, 1 H) benzo- nitrile2,2,2- trifluoro- acetate E297 5-(((2-d- Amino- cyclo- propane-carbonyl)- 9-oxo- 2,3,4,9, 11,11a- hexa- hydro-1H- pyrazino-

C 0.55 425.0 (CD₃OD) δ ppm 1.36-1.50 (m, 4 H) 2.68 (s, 3H) 3.25 (m., 2H) 3.47-3.59 (m, 1 H) 3.91 (m, 1 H) 4.07-4.21 (m, 1 H) 4.30- 4.45 (m, 2H) 4.47-4.54 (m, 1 H) 4.61-4.72 [1′,2′:3,4]- (m, 1 H) 5.43 (s, imidazo-2 H) 6.07 (s, 1H) [1,2-c]- 7.48 (t, J = 8.91 pyrimidin- Hz, 1 H) 7.887-yl)oxy)- (m, 1 H) 7.95 methyl)-2- (dd, J = 6.02, fluoro- 2.26 Hz, 1 H)benzo- nitrile 2,2,2- trifluoro- acetate E298 5-(((2-(3- Amino-3-methyl- butanoyl)- 9-oxo-2, 3,4,9,11, 11a-hexa- hydro-1H- pyrazino-[1′,2′:3,4]-

C 0.56 441.2 (CD₃OD) δ ppm 1.33 (d, J = 8.53 Hz, 6 H) 2.55 (s, 3 H)2.63-2.84 (m, 3 H) 3.22- 3.42 (m, 2 H) 3.71-3.81 (m, 1 H) 3.94-4.31 (m,4 H) 4.61- 4.85 (m, 1 H) imidazo- 5.29 (s, 2 H) [1,2-c]- 5.93 (d, J =7.53 pyrimidin- Hz, 1 H) 7.35 7-yl)oxy)- (t, J = 8.91 Hz, methyl)- 1 H)7.74 (ddd, 2-fluoro- J = 8.53, 5.14, benzo- 2.13 Hz, 1 H) nitrile 7.81(dd, J = 2,2,2- 6.02, 2.26 Hz, trifluoro- 1 H) acetate E299 2-Acetyl-7-((3,5- difluoro- 4-((6- methyl- pyridin-3- yl)oxy)- benzyl)- oxy)-3,4,11,11a- tetra- hydro-1H- pyrazino- [1′,2′:3,4]-

B 0.59 484.1 (CDCl₃) δ ppm 2.20 (s, 3 H) 2.54 (s, 3 H) 2.56-2.80 (m, 1H) 3.11-3.36 (m, 2 H) 3.56 (m, 1 H) 3.80 (dd, J = 12.05, 6.27 Hz, 1 H)3.84-4.06 (m, 2 H) 4.26 (d, J = 11.04 Hz, 1 H) 4.72-4.94 (m, 1 H) 5.11(d, J = imidazo- 10.79 Hz, 1 H) [1,2-c]- 5.41 (m, 2 H) pyrimidin-7.01-7.20 (m, 9(2H)-one 4 H) 8.29 (d, J = 2.51 Hz, 1 H) E300 Methyl-7-((3,4-di- fluoro- benzyl)- oxy)-9- oxo-3,4, 11,11a- tetrahydro-1H-pyrazino- [1′,2′:3,4]- imidazo- [1,2-c]-

B 0.71 393.0 (CDCI₃) δ ppm 2.76-3.02 (m, 2 H) 3.21 (m, 1 H) 3.46 (m, 1H) 3.67-3.81 (m, 4 H) 3.91 (m, 1 H) 4.13- 4.43 (m, 3 H) 5.04 (s, 1 H)5.28-5.40 (m, 2 H) 7.10-7.26 (m, 3 H) pyrimidine 2(9H)-car- boxylateE301 7-((3,4- Difluoro- benzyl)- oxy)-N,N- dimethyl- 9-oxo-3,4, 11,11a-tetrahydro- 1H- pyrazino- [1′,2′:3,4]- imidazo- [1,2-c]

B 0.65 406.1 (CDCl₃) δ ppm 2.77-3.02 (m, 8 H) 3.33 (dd, J = 12.05, 3.26Hz, 1 H) 3.37- 3.48 (m, 1 H) 3.64-3.82 (m, 3 H) 3.96-4.08 (m, 1 H) 4.21(dd, J = 11.80, 8.78 Hz, 1 H) 5.02 (s, 1 H) 5.27-5.41 (m, pyrimidine 2H) 7.11-7.26 2(9H)-car- (m, 3 H) boxamide E302 5-(((2- (Cyclo- butane-carbonyl)- 9-oxo-2,3, 4,9,11,11a- hexahydro- 1H- pyrazino- [1′,2′:3,4]-imidazo- [1,2-c] pyrimidin-

E 0.71 424.1 (CDCl₃) δ ppm 1.85-2.12 (m, 2 H) 2.22 (m, 2 H) 2.38 (m, 2H) 2.54-2.80 (m, 1 H) 3.00- 3.38 (m, 3 H) 3.52 d, J = 10.29 Hz, 1 H)3.67-3.95 (m, 3 H) 4.23 (dd, J = 11.80, 8.53 Hz, 1 H) 4.67- 7-yl)oxy)-4.94 (m, 1 H) methyl)-2- 5.06 (d, J = fluoro- 14.05 Hz, 1 H) benzo-5.35-5.51 (m, nitrile 2 H) 7.22 (t, J = 8.53 Hz, 1 H) 7.61-7.72 (m, 2 H)E303 1-(7-((3,4- Difluoro- benzyl)- oxy)-9- oxo-3,4, 11,11a- tetrahydro-1H- pyrazino- [1′,2′:3,4]- imidazo- [1,2-c] pyrimidin-

E 0.83 433.2 (CD₂Cl₂) δ ppm 1.17 (t, J = 7.65 Hz, 6 H) 2.73- 2.94 (m, 1H) 3.08-3.34 (m, 3 H) 3.48-3.91 (m, 3 H) 3.91- 4.08 (m, 1 H) 4.08-4.26(m, 1 H) 4.57-4.77 (m, 1 H) 5.10 (m, 1 H) 5.30- 5.36 (m, 2 H) 2(9H)yl)-7.13-7.25 (m, 3-methyl- 2 H) 7.25-7.35 butane- (m, 1 H) 1,2-dione E3047-((3,4- Difluoro- benzyl)- oxy)-2- propyl-3,4, 11,11a- tetrahydro- 1H-pyrazino- [1′,2′:3,4]- imidazo- [1,2-c]- pyrimidin-

A 0.63 377.1 (CD₂Cl₂) δ ppm 0.93 (t, J = 7.28 Hz, 3 H) 1.52 (sxt, J =7.38 Hz, 2 H) 1.96- 2.07 (m, 1 H) 2.12 (td, J = 11.67, 3.51 Hz, 1 H)2.38 (m, 2 H) 2.85 (d., J = 11.54 Hz, 1 H) 2.99 (dd, J = 11.17, 2.389(2H)-one Hz, 1 H) 3.29 (td, J = 12.55, 3.51 Hz, 1 H) 3.42-3.51 (m, 1 H)3.67 (dd, J = 11.42, 5.65 Hz, 1H) 3.95- 4.07 (m, 1 H) 4.07-4.16 (m, 1 H)5.02 (s, 1 H) 5.34 (m, 2 H) 7.07-7.26 (m, 2 H) 7.26- 7.35 (m, 1 H) E3057-((3,4- Difluoro- benzyl)- oxy)-2- isobutyl- 3,4,11, 11a-tetra-hydro-1H- pyrazino- [1′,2′:3,4]- imidazo- [1,2-c]- pyrimidin-

A 0.63 391.2 (CD₂Cl₂) δ ppm 0.93 (d, J = 6.53 Hz, 6 H) 1.75- 1.87 (m, 1H) 1.98-2.19 (m, 4 H) 2.78-2.85 (m, 1H) 2.91- 3.00 (m, 1 H) 3.25-3.34(m, 1 H) 3.41-3.50 (m, 1 H) 3.61- 3.72 (m, 1 H) 3.97-4.07 (m, 9(2H)-one1 H) 4.06-4.16 (m, 1 H) 5.02 (s, 1 H) 7.15-7.24 (m, 2 H) 7.25- 7.34 (m,1 H); E306 Ethyl 7- ((3,4- difluoro- benzyl)- oxy)-9- oxo-3,4, 11,11a-tetrahydro- 1H- pyrazino- [1′,2′:3,4]- imidazo- [1,2-c]-

B 0.76 407.1 (CDCl₃) δ ppm 1.25-1.35 (m, 3 H) 2.77-3.02 (m, 2 H) 3.22(td, J = 12.61, 3.39 Hz, 1 H) 3.47 (m, 1 H) 3.75 (dd, J = 11.80, 6.53Hz, 1 H) 3.84-3.98 (m, 1 H) 4.11- 4.49 (m, 5 H) 5.05 (s, 1 H) pyrimidine5.27-5.46 (m, 2(9H)-car- 2 H) 7.09-7.28 boxylate (m, 3 H) E307 Isopropyl7-((3,4- difluoro- benzyl)- oxy)-9- oxo-3,4, 11,11a- tetrahydro- 1H-pyrazino- [1′,2′:3,4]- imidazo- [1,2-c]-

B 0.82 421.3 (CDCl₃) δ ppm 1.30 (d, J = 6.27 Hz, 6 H) 2.73- 3.00 (m, 2H) 3.14-3.28 (m, 1H) 3.42-3.54 (m, 1 H) 3.75 (dd, J = 11.80, 6.53 Hz, 1H) 3.85- 3.98 (m, 1 H) 4.19-4.40 (m, 3 H) 4.93-5.02 (m, 1 H) 5.05pyrimidine (s, 1 H) 5.37 2(9H)-car- (m, 2 H) 7.10- boxylate 7.27 (m, 3H) E308 7-((3,4- Difluoro- benzyl)- oxy)-2-(1- (methyl- amino)- cyclo-propane- carbonyl)- 3,4,11,11a- tetrahydro- 1H- pyrazino-

C 0.57 432.2 (CD₂Cl₂) δ ppm 0.79 (br. s., 2H) 1.07 (br. s., 2 H) 2.39(s, 3 H) 2.79-3.05 (m, 2 H) 3.20-3.33 (m, 1 H) 3.47- 3.59 (m, 1 H)3.67-3.80 (m, 1H) 3.91-4.05 (m, 1 H) 4.12- 4.24 (m, 1H) 4.59-4.73 (m,[1′,2′:3,4]- 1 H) 4.73-4.87 imidazo- (m, 1 H) 5.08 [1,2-c] (s, 1 H) 7.21(m, pyrimidin- 2 H) 7.25-7.36 9(2H)-one (m, 1H)

E309

Method F

7-((3,4-Difluorobenzyl)amino)-2-(methylsulfonyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

To7-chloro-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one(444 mg, 1.959 mmol) in DCM (15 mL) at 0° C. was added TEA (1.5 mL,10.76 mmol) and then MsCl (0.19 mL, 2.438 mmol) dropwise. The reactionwas stirred for 5 hrs, and then concentrated. The crude product waspurified on a Combiflash silica cartridge (12 g) (0-5% MeOH/DCM) to givethe intermediate7-chloro-2-(methylsulfonyl)-3,4,11,11a-tetrahydro-1Hpyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one(665 mg, 0.873 mmol, 44.6% yield) as an amorphous tan solid. (LC/MS: m/z304.9 (M+H)⁺, 0.41 min (ret. time)) A mixture of the intermediate (0.151mL, 0.368 mmol), (3,4-difluorophenyl)methanamine (0.13 mL, 1.099 mmol)and DIPEA (0.32 mL, 1.832 mmol) in 1-Butanol (1.8 mL) (in threeportions), and added to a microwave vial and the reaction vessel wassealed and heated in Biotage Initiator using initial high to 120° C. for30 min. After cooling the reaction, the mixture was concentrated Thecrude was purified on a Combiflash silica cartridge (12 g) [0-20% (10%NH₄OH/MeOH)/DCM] then by prep reverse phase HPLC [10-90% CH₃CN/H₂O (0.1%NH₄OH)] to give the title compound (18 mg, 0.044 mmol, 11.90% yield) asan amorphous white solid.

LC/MS: m/z 412.2 (M+H)⁺, 0.59 min (ret. time).

¹H NMR (400 MHz, CD₃OD): δ 2.76-2.97 (m, 5H) 3.25-3.31 (m, 1H) 3.64-3.77(m, 3H) 3.90 (d, J=11.80 Hz, 1H) 3.99-4.18 (m, 2H) 4.52 (br. s., 2H)5.08 (s, 1H) 7.08-7.31 (m, 3H)

E310

Method G

7-((3,4-Difluorobenzyl)oxy)-2-isobutyryl-3,4,11,11a-tetrahydro-1Hpyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

The title compound was prepared by a procedure similar to that describedfor E310 starting from7-chloro-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-oneand isobutyryl chloride.

LC/MS: m/z 405.0 (M+H)⁺, 0.73 min (ret. time).

¹H NMR (400 MHz, CD₂Cl₂) δ ppm 1.12 (br. s., 6H) 2.45-2.87 (m, 2H)2.98-3.28 (m, 2H) 3.51 (d, J=10.54 Hz, 1H) 3.69 (dd, J=11.67, 6.40 Hz,1H) 3.77-4.23 (m, 3H) 4.55-4.93 (m, 1H) 5.05 (s, 1H) 5.25-5.37 (m, 2H)7.07-7.33 (m, 3H)

The following compounds E311-E315 listed in Table 4 were prepared by aprocedure similar to that described for E309-E310 starting from therequisite acid chloride or sulfonyl chloride, and benzyl alcohol orbenzyl amine:

TABLE 4 LC/MS Method ret. ¹H NMR Ex # Name Structure Used Time MS (400MHz) E311 7-((2,3- Difluorobenzyl) amino)-2- (methylsulfonyl)- 3,4,11,11a-tetrahydro- 1H- pyrazino[1′,2′:3,4] imidazo[1,2- c]pyrimidin-9(2H)-one

F 0.59 412.2 (CD₃OD) δ ppm 2.76- 2.97 (m, 5 H) 3.27-3.31 (m, 1H)3.65-3.79 (m, 3 H) 3.91 (d, J = 12.05 Hz, 1 H) 4.00-4.17 (m, 2 H) 4.64(br. s., 2 H) 5.11 (br. s., 1 H) 7.06- 7.25 (m, 3 H) E312 2-Fluoro-5-(((2- (methylsulfonyl)- 9-oxo- 2,3,4,9,11,11a- hexahydro-1H-pyrazino[1′,2′:3,4] imidazo[1,2- c]pyrimidin-7- yl)amino) methyl)benzonitrile

F 0.55 419.0 (DMSO-d₆) δ ppm 2.67- 2.87 (m, 2 H) 2.92 (s, 3 H) 3.15-3.25(m, 1 H) 3.49- 3.58 (m, 2 H) 3.61-3.75 (m, 2 H) 3.88-3.99 (m, 2 H) 4.42-4.54 (m, 2 H) 4.95-5.03 (m, 1 H) 7.46-7.54 (m, 1 H) 7.56-7.65 (m, 1 H)7.66-7.73 (m, 1 H) 7.74-7.83 (m, 1 H) E313 7-((3,4- Difluorobenzyl)oxy)-2- (methylsulfonyl)- 3,4,11,11a- tetrahydro-1H- pyrazino[1′,2′:3,4]imidazo[1,2- c]pyrimidin- 9(2H)-one

G 0.65 413.2 (CHLOROFORM- d) δ ppm 2.70- 2.95 (m, 5 H) 3.34-3.49 (m, 1H) 3.59 (d, J = 13.30 Hz, 1 H) 3.80 (dd, J = 11.80, 5.52 Hz, 1 H) 3.87(d, J = 11.04 Hz, 1 H) 3.98 (d, J = 12.05 Hz, 1 H) 4.04-4.19 (m, 1 H)4.25 (dd, J = 11.42, 8.91 Hz, 1 H) 5.07 (s, 1 H) 5.30-5.45 (m, 2 H)7.10- 7.28 (m, 3 H) E314 5-(((2- Acetyl-9-oxo- 2,3,4,9,11,11a-hexahydro-1H- pyrazino[1′,2′:3,4] imidazo[1,2- c]pyrimidin-7- yl)amino)methyl)-2- fluoro- benzonitrile

F 0.53 383.0 (CD₃CN, D₂O) δ ppm 2.09 (s, 3 H) 2.61 (s, 1 H) 3.00- 3.24(m, 2 H) 3.54-3.64 (m, 2 H) 3.78-4.10 (m, 3 H) 4.47 (br. s., 3 H) 4.99(br. s., 1 H) 7.31 (t, J = 8.91 Hz, 1 H) 7.61- 7.76 (m, 2 H) E3152-Acetyl- 7-((3,4- difluorobenzyl) oxy)- 3,4,11,11a- tetrahydro-1H-pyrazino[1′,2′:3,4] imidazo[1,2- c]pyrimidin- 9(2H)-one

G 0.63 377.0 (D₂O) δ ppm 2.55- 2.63 (m, 1 H) 2.71 (s, 3 H) 3.21- 3.41(m, 1 H) 3.66- 3.91 (m, 2 H) 4.16- 4.34 (m, 2 H) 4.44- 4.73 (m, 3 H)4.99- 5.23 (m, 1 H) 5.79- 5.91 (m, 3 H) 7.80- 8.00 (m, 3 H)

E3162-Cyclobutoxy-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile

To an ice-cold solution of 2-cyclobutoxy-5-formylbenzonitrile (0.06 g,0.298 mmol) in 2-MeTHF (0.550 mL) was added a fresh solution of NaBH₄(0.017 g, 0.447 mmol) in 0.1% wt. NaOH in water (4.5 mL) and thereaction was stirred for 1 h. The mixture was quenched with saturatedNH₄Cl. The aqueous layer was extracted with EtOAc (3 times). Thecombined organics were washed with brine, dried (anhydrous Na₂SO₄),filtered, and concentrated under reduced pressure to provide the benzylalcohol. To a solution of the benzyl alcohol, tert-Butyl7-chloro-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2(9H)-carboxylate (0.132 g, 0.298 mmol) in 2-MeTHF (1.832 mL)was added NaH (0.030 g, 0.745 mmol) and the reaction was stirred at roomtemperature for 1 h. The reaction was quenched by addition of saturatedNH₄Cl. The layers were separated and the aqueous layer was extractedwith EtOAc (3 times). The combined organic layers were concentrated. Thecrude was purified on a Combiflash silica cartridge (12 g) (0-15%MeOH/DCM) to give the intermediate tert-butyl7-((3-cyano-4-cyclobutoxybenzyl)oxy)-9-oxo-3,4,11,11a-tetrahydro-1Hpyrazino[1′,2′:3,4]imidazo[1,2c] pyrimidine-2(9H)-carboxylate (170 mg, 0.148 mmol, 49.7% yield) as aglassy solid film. (LC/MS: m/z 494.2 (M+H)⁺, 0.96 min (ret. time)) Tothis intermediate (130 mg, 0.263 mmol) was added HCl (3M in CPME) (878μl, 2.63 mmol). The mixture was stirred for 1 h and then concentrated.The crude was purified by prep reverse phase [10-90% CH₃CN/H₂O (0.1%NH₄OH)] to give the title compound (15 mg, 0.038 mmol, 14.47% yield) asan amorphous white powder.

LC/MS: m/z 394.1 (M+H)⁺, 0.68 min (ret. time).

¹H NMR (400 MHz, CDCl₃): δ ppm 1.63-1.81 (m, 2H) 1.91 (q, J=10.29 Hz,1H) 2.26 (quin, J=9.85 Hz, 2H) 2.41-2.53 (m, 2H) 2.60-2.83 (m, 2H) 3.02(d, J=12.05 Hz, 1H) 3.13-3.28 (m, 2H) 3.42 (d, J=11.54 Hz, 1H) 3.68 (dd,J=11.54, 6.53 Hz, 1H) 3.92 (d, J=8.78 Hz, 1H) 4.17 (dd, J=11.29, 9.03Hz, 1H) 4.72 (quin, J=7.03 Hz, 1H) 4.96 (s, 1H) 5.24-5.39 (m, 2H) 6.78(d, J=8.78 Hz, 1H) 7.53 (d, J=8.78 Hz, 1H) 7.59 (s, 1H)

E3172-(Cyclopentyloxy)-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E316 starting from 2-(cyclopentyloxy)-5-formylbenzonitrile andtert-butyl7-chloro-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2(9H)-carboxylate.

LC/MS: m/z 408.0 (M+H)⁺, 0.72 min (ret. time).

¹H NMR (400 MHz, CDCl₃): δ ppm 1.54-2.00 (m, 8H) 2.71-3.00 (m, 2H)3.11-3.57 (m, 4H) 3.71 (d, J=6.02 Hz, 1H) 4.17 (d, J=9.54 Hz, 2H) 4.85(br. s., 1H) 5.02 (s, 1H) 5.20-5.35 (m, 2H) 6.93 (d, J=8.78 Hz, 1H)7.46-7.62 (m, 2H)

E3187-(2,3-Difluorophenethyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

A solution of tert-butyl7-((2,3-difluorophenyl)ethynyl)-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2(9H)-carboxylate (40 mg, 0.093mmol) and palladium on carbon (10%) (1.987 mg, 1.867 μmol) in methanol(5 mL) was placed under H₂ (balloon) at room temperature for 1 h. Thereaction was filtered through celite. The filtrate was concentrated andthen dissolved in TFA (0.5 mL, 6.49 mmol). The mixture was then stirredfor 5 min at room temperature and concentrated. The crude was purifiedby reverse phase prep HPLC [10-90% CH₃CN/H₂O (0.1% TFA] to give thetitle compound (22 mg, 0.066 mmol, 70.9% yield) as an amorphous whitesolid.

LC/MS: m/z 333.3 (M+H)⁺, 0.45 min (ret. time).

¹H NMR (400 MHz, CDCl₃): δ ppm 1.81 (br. s., 1H) 2.61-2.82 (m, 4H)2.97-3.14 (m, 3H) 3.13-3.30 (m, 2H) 3.38-3.53 (m, 1H) 3.72 (dd, J=12.05,6.78 Hz, 1H) 3.87-4.05 (m, 1H) 4.21 (dd, J=11.80, 9.54 Hz, 1H) 5.31 (s,1H) 6.88-7.08 (m, 3H)

E3192-Fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)amino)methyl)benzonitrilehydrochloride

A mixture of tert-Butyl7-chloro-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2(9H)-carboxylate (200 mg, 0.612 mmol),(3,4-difluorophenyl)methanamine (0.13 mL, 1.099 mmol) and DIPEA (0.32mL, 1.832 mmol) in 1-butanol (3 mL) was added to a microwave vial andthe reaction vessel was sealed and heated in Biotage Initiator to 120°C. for 30 min. After cooling to room temperature, the mixture wasconcentrated and the crude was purified on a Combiflash silica cartridge(12 g) [0-20% MeOH (10% NH₄OH)/DCM] to give the N-Boc protected product.The intermediate was dissolved in HCl (4N in dioxane) (1.530 mL, 6.12mmol) and stirred for 30 min at room temperature. The reaction wasconcentrated and the crude was purified by reverse phase prep HPLC(10-90% CH₃CN/H₂O) to give the title compound (40 mg, 0.106 mmol, 17.34%yield) as a lightly colored amorphous solid.

LC/MS: m/z 341.0 (M+H)⁺, 0.32 min (ret. time).

¹H NMR (400 MHz, CD₃CN): δ 1.53 (d, J=5.27 Hz, 2H) 3.28-3.47 (m, 2H)3.67-3.97 (m, 3H) 4.07 (dd, J=11.29, 6.78 Hz, 1H) 4.19 (dd, J=14.31,3.01 Hz, 1H) 4.54 (t, J=10.42 Hz, 1H) 4.68 (d, J=9.03 Hz, 1H) 4.79 (s,2H) 5.45 (br. s., 1H) 7.61 (t, J=8.78 Hz, 1H) 7.84-8.02 (m, 2H)

E3207-((3,4-Difluorobenzyl)oxy)-2-methyl-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

To a solution of7-((3,4-difluorobenzyl)oxy)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one(20 mg, 0.060 mmol) in DCM (0.5 mL) was added DIPEA (0.03 mL, 0.172mmol) then MeI (0.01 mL, 0.160 mmol) at room temperature. The reactionwas stirred at room temperature for 1.5 hrs, then diluted with DCM andquenched by addition of saturated NaHCO₃. Layers were separated and theorganic layer was further washed with saturated NaHCO₃ (2 times). Theorganic layer was then dried over anhydrous Na₂SO₄, filtered, andconcentrated. The crude was purified on a Combiflash silica cartridge(12 g) [0-10% (10% NH₄OH/MeOH)/DCM] to give the title compound (11 mg,0.032 mmol, 52.8% yield) as an amorphous white powder.

LC/MS: m/z 349.0 (M+H)⁺, 0.55 min (ret. time).

¹H NMR (400 MHz, CDCl₃): δ ppm 2.02 (m, 2H) 2.36 (s, 3H) 2.74-2.84 (m,1H) 2.88-2.99 (m, 1H) 3.27-3.38 (m, 1H) 3.41-3.51 (m, 1H) 3.71-3.80 (m,1H) 3.99-4.10 (m, 1H) 4.17 (m, 1H) 5.01 (s, 1H) 5.36 (m, 2H) 7.11-7.26(m, 3H)

E3217-((3,5-Difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-2-methyl-3,4,11,11a-tetrahydro-1Hpyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

The title compound was prepared by a procedure similar to that describedfor7-((3,4-difluorobenzyl)oxy)-2-methyl-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one starting from7-Chloro-2-methyl-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-oneand (3,5-Difluoro-4-((6-methylpyridin-3-yl)oxy)phenyl)methanol

LC/MS: m/z 456.1 (M+H)+, 0.56 min (ret. time).

¹H NMR (400 MHz, CDCl₃): δ ppm 1.98-2.09 (m, 1H) 2.09-2.20 (m, 1H) 2.37(s, 3H) 2.54 (s, 3H) 2.77-2.87 (m, 1H) 2.89-2.99 (m, 1H) 3.29-3.40 (m,1H) 3.44-3.53 (m, 1H) 3.70-3.81 (m, 1H) 3.99-4.12 (m, 1H) 4.14-4.24 (m,1H) 5.05 (s, 1H) 5.41 (m, 2H) 7.04-7.19 (m, 4H) 8.30 (m, 1H)

E3222-Fluoro-5-(((9-oxo-2-(2,2,2-trifluoroethyl)-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile

To a solution of2-fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile(46 mg, 0.135 mmol) in THF (0.7 mL) and NMP (0.5 mL) was added lithiumbis(trimethylsilyl)amide (1 M in THF) (0.14 mL, 0.140 mmol) at 0° C.slowly. After 15 min at 0° C., 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.02 mL, 0.139 mmol) was added. After 1.25 h,DIPEA (0.024 mL, 0.135 mmol) and an additional aliquot of2,2,2-trifluoroethyl trifluoromethanesulfonate (0.02 mL, 0.139 mmol)were added. After 42 hrs the reaction was concentrated and the residuewas partitioned between saturated NaHCO₃ and EtOAc. The layers wereseparated and the aqeuous layer further extracted with EtOAc. Thecombined organic layers were washed with brine, then dried overanhydrous Na₂SO₄, filtered, and concentrated. The crude was purified ona Combiflash silica cartridge (24 g) [0-10% (10% NH₄OH/MeOH)/DCM] thenby prep reverse phase HPLC [10-90% CH₃CN/H₂O to 90% CH₃CN/H₂O] to givethe title compound (7 mg, 0.017 mmol, 12.27% yield) as an amorphouswhite solid.

LC/MS: m/z 424.1 (M+H)⁺, 0.78 min (ret. time).

¹H NMR (400 MHz, CDCl₃): δ ppm 2.54 (t, J=10.79 Hz, 1H) 2.64 (td,J=11.48, 2.89 Hz, 1H) 2.89-3.19 (m, 4H) 3.29-3.41 (m, 1H) 3.43-3.52 (m,1H) 3.74 (dd, J=11.54, 5.77 Hz, 1H) 3.97-4.12 (m, 1H) 4.12-4.25 (m, 1H)5.03 (s, 1H) 5.31-5.48 (m, 2H) 7.21 (t, J=8.53 Hz, 1H) 7.61-7.73 (m, 2H)

E3232-Fluoro-5-(((9-oxo-2-(2,2,2-trifluoroacetyl)-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile

To a solution of2-fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile(203 mg, 0.357 mmol) and2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (90 mg, 0.443mmol) in DCM (3 mL) at room temperature was added first DIPEA (0.2 mL,1.145 mmol) followed by T3P (50 wt. % in EtOAc) (0.25 mL, 0.420 mmol).The reaction was stirred for 16 h at room temperature then diluted withDCM (3 mL), washed with saturated NH₄Cl (2 mL, two times), saturatedNaHCO₃ (2 mL, two times), brine (2 mL), dried over anhydrous sodiumsulfate, filtered. The crude was purified by prep reverse phase HPLC[10-90% CH₃CN/H₂O (0.1% TFA)] to give the title compound (90 mg, 0.206mmol, 57.7% yield) as a tan amorphous solid.

LC/MS: m/z 438.0 (M+H)⁺, 0.76 min (ret. time).

E3242-(7-((3-Cyano-4-fluorobenzyl)oxy)-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-2(9H)-yl)acetic Acid, Trifluoroacetic Acid Salt

To a solution of2-fluoro-5-(((9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile(40 mg, 0.117 mmol) in DCM (0.4 mL) was added TEA (0.1 mL, 0.717 mmol)and tert-butyl 2-bromoacetate (0.03 mL, 0.203 mmol). After 18 h thereaction was diluted with DCM, then washed with H₂O (3 times) and brine,then dried over anhydrous Na₂SO₄, filtered and concentrated. Thenanhydrous DCM (0.5 mL) was added by syringe followed by addition of TFA(0.5 mL, 6.49 mmol). The reaction was stirred for 30 min andconcentrated. The residue was purified by prep reverse phase HPLC[10-90% CH₃CN/H₂O (0.1% TFA)] to afford the title compound (16 mg, 0.031mmol, 26.6% yield) as a white amorphous.

LC/MS: m/z 399.9 (M+H)⁺, 0.55 min (ret. time).

¹H NMR (400 MHz, CD₃OD): δ ppm 2.83-3.05 (m, 2H) 3.39 (m., 1H) 3.48-3.82(m, 4H) 3.89 (dd, J=11.29, 7.28 Hz, 1H) 4.14 (m, 1H) 4.37 (t, J=10.79Hz, 1H) 4.54 (m, 1H) 5.42 (s, 2H) 7.47 (t, J=8.91 Hz, 1H) 7.82-7.90 (m,1H) 7.93 (d, J=6.02 Hz, 1H)

E3253-(7-((3-Cyano-4-fluorobenzyl)oxy)-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-2(9H)-yl)propanoic Acid

The title compound was prepared by a procedure similar to that describedfor E324 starting from tert-butyl 3-bromopropanoate.

LC/MS: m/z 415.0 (M+H)⁺, 0.55 min (ret. time).

¹H NMR (400 MHz, D₂O): δ 2.99 (t, J=6.65 Hz, 2H) 3.41 (t, J=11.92 Hz,2H) 3.64 (t, J=6.78 Hz, 2H) 3.86 (m, 2H) 3.95-4.11 (m, 2H) 4.31 (d,J=14.81 Hz, 1H) 4.52 (t, J=11.04 Hz, 1H) 5.42 (s, 2H) 5.96 (s, 1H) 7.43(t, J=8.91 Hz, 1H) 7.82 (m, 1H) 7.89 (d, J=5.77 Hz, 1H)

E326 and E327 E326: Isomer 1: Ethyl2-(7-((3,4-difluorobenzyl)oxy)-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4] imidazo[1,2-c]pyrimidin-2(9H)-yl)propanoate (E326) E327:Isomer 2:Ethyl2-(7-((3,4-difluorobenzyl)oxy)-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4] imidazo[1,2-c]pyrimidin-2(9H)-yl)propanoate (E327)

To a solution of7-((3,4-difluorobenzyl)oxy)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one (150 mg, 0.449 mmol) in DMF (1.3 mL) wasadded ethyl 2-bromopropanoate (0.070 mL, 0.538 mmol) and DIPEA (0.157mL, 0.897 mmol) by syringe under argon. The reaction was heated to 110°C. with stirring for 3.75 hrs. The reaction was diluted with water andextracted with EtOAc. The combined organic layers were concentrated andthe crude product was purified on a Combiflash silica cartridge (12 g)(0-15% MeOH/DCM) then by prep reverse phase HPLC [10-90% CH₃CN/H₂O (0.1%TFA)] to give the title compound of isomer 1 (15 mg, 0.035 mmol, 7.70%yield) as an amorphous white solid and the mixture of isomer 1 andisomer 2 (21 mg, 0.048 mmol, 10.77% yield) as a sticky solid.

E326 (isomer 1): LC/MS: m/z 435.1 (M+H)⁺, 0.84 min (ret. time).

¹H NMR (400 MHz, CD₂Cl₂) δ ppm 1.16-1.35 (m, 6H) 2.30-2.65 (m, 2H) 2.83(t, J=12.30 Hz, 1H) 3.01 (t, J=13.18 Hz, 1H) 3.10-3.26 (m, 1H) 3.32-3.45(m, 2H) 3.51-3.62 (m, 1H) 3.77-3.96 (m, 1H) 3.99-4.19 (m, 3H) 4.70 (s,1H) 4.93 (s, 2H) 7.01-7.13 (m, 1H) 7.17 (br. s., 1H) 7.21-7.33 (m, 1H).

E327 (isomer 2): LC/MS: m/z 435.2 (M+H)⁺, 0.80 min (ret. time);

¹H NMR (400 MHz, CD₂Cl₂) δ ppm 1.17-1.35 (m, 6H) 2.47 (m, 2H) 2.75-2.91(m, 1H) 2.92-3.07 (m, 1H) 3.14-3.31 (m, 1H) 3.32-3.49 (m, 2H) 3.59-3.70(m, 1H) 3.87-4.18 (m, 4H) 4.98 (m, 1H) 7.15 (m, 2H) 7.21-7.31 (m, 1H).

E3282-Cyclopropyl-2-(7-((3,4-difluorobenzyl)oxy)-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-2(9H)-yl)acetic Acid, TrifluoroaceticAcid Salt

To a solution of7-((3,4-difluorobenzyl)oxy)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one(50 mg, 0.150 mmol) and 2-cyclopropyl-2-oxoacetic acid (68 mg, 0.596mmol) in dichloromethane (1 mL) was added acetic acid (4 μl, 0.070mmol). The reaction was stirred for 30 min, then sodiumtriacetoxyborohydride (63 mg, 0.297 mmol) (100 μl) were added followedby water. The mixture was stirred for an additional 18 h. The reactionwas diluted with H₂O (1 mL) and basified to pH 12 by addition of 1 NNaOH. The layers were separated and the aqeuous phase was washed withEtOAc (2×0.5 mL). The aqeuous phase was then acidified to pH 4 with 1 NHCl and washed with EtOAc (3×0.5 mL). The aqeuous layer was furtheracidified to pH 1 with 1N HCl, saturated with NaCl, and extracted withEtOAc 4 times). The combined organic layers were dried over anhydroussodium sulfate, filtered, and concentrated. The crude was purified byprep reverse phase HPLC [10-90% CH₃CN/H₂O (0.1% TFA)] to give the titlecompound (12 mg, 0.022 mmol, 14.68% yield) as a 51:49 mixture of racemicdiastereomers

Isomer 1: LC/MS: m/z 433.1 (M+H)⁺, 0.62 min (ret. time);

Isomer 2 LC/MS: m/z 433.1 (M+H)⁺, 0.64 min (ret. time).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.25-0.45 (m, 2H) 0.53-0.72 (m, 2H) 1.06(d, J=3.76 Hz, 1H) 2.67 (m, 2H) 3.12-3.76 (m, 3H) 3.97 (br. s., 1H)4.07-4.32 (m, 2H) 4.47 and 4.76 (s, 1H) 5.30 (s, 2H) 5.83 (br. s., 1H)7.25-7.63 (m, 3H)

E3292-Fluoro-5-(((9-oxo-1,3,4,9,11,11a-hexahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-7-yl)oxy)methyl)benzonitrile

To a solution of7-chloro-3,4,11,11atetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one(100 mg, 0.439 mmol) and 2-fluoro-5-(hydroxymethyl)benzonitrile (66.4mg, 0.439 mmol) in anhydrous 2-Me-THF (3 mL) was added NaH (49 mg, 1.225mmol). The reaction was stirred at room temperature for 1.5 h and themixture was quenched with saturated NH₄Cl (2 mL). The precipitate formedwas filtered and the filtercake was washed with EtOAc (2×3 mL) and DCM(2×2 mL). The layers of the filtrate were separated, and the aqueouslayer was extracted with EtOAc (2×2 mL). The filter cake was combinedwith the organic layers. Isolute was added to the combined organiclayers, and the mixture was concentrated. The crude was then purified byflash chromatography and then reverse phase HPLC to give the titlecompound (57.5 mg, yield 37% as a white solid.

LC/MS: m/z 342.9 (M+H)⁺, 0.59 min (ret. time).

¹H NMR (400 MHz, CD₃OD): δ 7.79-7.68 (m, 2H), 7.27 (t, J=8.8 Hz, 1H),5.40-5.31 (m, 3H), 4.17-3.85 (m, 4H), 3.66-3.33 (m, 5H)

E3302-(Cyclopropanecarbonyl)-7-((3,4-difluorobenzyl)oxy)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

Cyclopropanecarbonyl chloride (20 μl, 0.218 mmol) was added to asolution of7-((3,4-difluorobenzyl)oxy)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one(50 mg, 0.150 mmol) and TEA (60 μl, 0.430 mmol) in anhydrous DCM (1 mL).The reaction was stirred at room temperature for 40 min. Additional DCM(2 mL) was added, and the mixture was washed with 10% citric acid (1×1mL) and saturated NaHCO₃ (1×1 mL). The mixture was concentrated and thecrude was then purified by flash chromatography to give 15.3 mg (25%) ofthe title compound.

LC/MS: m/z 403.0 (M+H)⁺, 0.69 min (ret. time).

¹H NMR (400 MHz, CD₃CN): δ 7.48-7.26 (m, 3H), 5.31 (s, 2H), 5.21 (s,1H), 4.84-4.34 (m, 2H), 4.24-3.61 (m, 4H), 3.34 (br. s., 2H), 2.93-2.68(m, 2H), 0.95-0.70 (m, 4H)

E3312-(Cyclopropylsulfonyl)-7-((3,4-difluorobenzyl)oxy)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

The title compound was prepared by a procedure similar to that describedfor E330 starting from cyclopropanesulfonyl chloride.

LC/MS: m/z 439.0 (M+H)⁺, 0.76 min (ret. time).

¹H NMR (400 MHz, CD₃CN) δ 7.49-7.21 (m, 3H), 5.29 (br. s., 2H), 5.21(br. s., 1H), 4.15 (br. s., 2H), 4.00-3.64 (m, 4H), 3.43-3.24 (m, 1H),3.17-2.96 (m, 2H), 2.55 (br. s., 1H), 1.04 (br. s., 4H)

E3327-((3,4-Difluorobenzyl)oxy)-2-pivaloyl-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

The title compound was prepared by a procedure similar to that describedfor E330 starting from pivaloyl chloride.

LC/MS: m/z 419.0 (M+H)⁺, 0.79 min (ret. time).

¹H NMR (400 MHz, CD₃CN) δ 7.39-7.15 (m, 3H), 5.26 (s, 2H), 5.10 (s, 1H),4.55-4.31 (m, 2H), 4.04 (dd, J=9.0, 11.5 Hz, 1H), 3.94-3.83 (m, 1H),3.62 (dd, J=6.0, 11.8 Hz, 2H), 3.18-3.07 (m, 1H), 2.95-2.77 (m, 2H),1.31-1.20 (m, 9H)

E3332-(1-Aminocyclopropanecarbonyl)-7-((3,4-difluorobenzyl)oxy)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-oneHydrochloride

1H-Pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2-carbonyl)cyclopropyl)carbamate(33.5 mg, 0.065 mmol) was added to a solution of 4 M HCl in dioxane (1mL, 4.00 mmol). The reaction was stirred at room temperature. After 20min, the reaction mixture was concentrated to give 12.6 mg (41%) of thetitle compound.

LC/MS: m/z 418.0 (M+H)⁺, 0.50 min (ret. time).

¹H NMR (400 MHz, CD₃OD): δ 7.51-7.42 (m, 1H), 7.38-7.32 (m, 2H), 6.05(s, 1H), 5.38 (s, 2H), 4.67-4.60 (m, 1H), 4.47 (d, J=12.0 Hz, 1H),4.40-4.33 (m, 2H), 4.20-4.10 (m, 1H), 3.89 (d, J=4.3 Hz, 1H), 3.76-3.71(m, 1H), 3.70-3.67 (m, 1H), 3.49 (dd, J=3.6, 13.2 Hz, 1H), 1.50-1.43 (m,2H), 1.41-1.35 (m, 2H)

Example E3342-(3-Amino-3-methylbutanoyl)-7-((3,4-difluorobenzyl)oxy)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

The title compound was prepared by a procedure similar to that describedfor E333 starting from1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-2(9H)-yl)-2-methyl-4-oxobutan-2-yl)carbamate.

LC/MS: m/z 434.0 (M+H)⁺, 0.55 min (ret. time).

¹H NMR (400 MHz, CD₃OD) δ 7.35 (dd, J=8.3, 10.8 Hz, 1H), 7.28-7.19 (m,2H), 5.35 (d, J=6.8 Hz, 1H), 5.30 (d, J=4.3 Hz, 2H), 4.80-4.58 (m, 1H),4.28-3.89 (m, 3H), 3.73 (dd, J=6.0, 10.8 Hz, 2H), 3.26-3.09 (m, 2H),2.82-2.67 (m, 1H), 2.56 (s, 2H), 1.24 (d, J=3.8 Hz, 6H)

E335 2-(2-Amino-2-methylpropanoyl)-7-((3,4-difluorobenzyl)oxy)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

The title compound was prepared by a procedure similar to that describedfor E333 starting from tert-butyl(1-(7-((3,4-difluorobenzyl)oxy)-9-oxo-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-2(9H)-yl)-2-methyl-1-oxopropan-2-yl).

LC/MS: m/z 420.1 (M+H)⁺, 0.58 min (ret. time).

¹H NMR (400 MHz, CD₃CN) δ 7.39-7.16 (m, 3H), 5.27 (s, 2H), 5.14-4.85 (m,3H), 4.08-3.99 (m, 1H), 3.97-3.86 (m, 1H), 3.64-3.50 (m, 2H), 3.15 (dt,J=3.3, 12.7 Hz, 1H), 2.92-2.71 (m, 2H), 1.59 (s, 2H), 1.33 (s, 6H)

E3367-((3,4-Difluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E329 starting from7-chloro-3,4,11,11atetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]oxazin-9(1H)-oneand (3,4-difluorophenyl)methanol.

LC/MS: m/z 336.1 (M+H)⁺, 0.60 min (ret. time).

¹H NMR (400 MHz, DMSO-d₆) δ 7.51-7.39 (m, 2H), 7.26 (br. s., 1H), 5.35(s, 1H), 5.24 (s, 2H), 4.03 (d, J=4.8 Hz, 1H), 3.99-3.92 (m, 1H), 3.88(dd, J=3.8, 11.3 Hz, 1H), 3.80 (dd, J=3.3, 11.3 Hz, 1H), 3.63 (d, J=13.3Hz, 1H), 3.52 (dd, J=5.5, 11.3 Hz, 1H), 3.43-3.34 (m, 2H), 3.29-3.20 (m,1H)

E3377-((3,4-Difluorobenzyl)oxy)-2-(3-(dimethylamino)propanoyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

A solution of 50 wt % T₃P in EtOAc (0.11 mL, 0.185 mmol) was addeddropwise to a solution of 3-(dimethylamino)propanoic acid hydrochloride(23 mg, 0.150 mmol),7-((3,4-difluorobenzyl)oxy)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one(50 mg, 0.150 mmol) and anhydrous TEA (0.08 mL, 0.577 mmol) in anhydrousDCM (1 mL). The reaction was stirred at room temperature. After 45 min,DCM (2 mL) was added, and the mixture was washed with saturated NaHCO₃(1×1 mL). The organic layer was concentrated the crude was then purifiedby flash chromatography to give 31.7 mg (49%) of the title compound as awhite solid.

LC/MS: m/z 434.2 (M+H)⁺ 0.54 min (ret. time).

¹H NMR (400 MHz, CD₃OD): δ 7.40-7.30 (m, 1H), 7.27-7.12 (m, 2H),5.38-5.27 (m, 3H), 4.64-4.47 (m, 1H), 4.19 (t, J=8.5 Hz, 2H), 4.03 (d,J=10.3 Hz, 1H), 3.79-3.68 (m, 2H), 3.23-3.12 (m, 1H), 2.71-2.57 (m, 4H),2.29 (s, 6H)

E3387-((3,4-Difluorobenzyl)oxy)-2-(2,2,2-trifluoroethyl)-3,4,11,11a-tetrahydro-1Hpyrazino [1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one trifluoroacetate

To a mixture of7-((3,4-difluorobenzyl)oxy)-3,4,11,11atetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one (50 mg, 0.150 mmol) and DIPEA (30 μl,0.172 mmol) in anhydrous THF (0.5 mL) was added 2,2,2-trifluoroethyltrifluoromethanesulfonate (36.2 mg, 0.156 mmol) in anhydrous THF (500μl). The vial was sealed, and the reaction was stirred at 70° C. Themixture was concentrated and the crude was then purified by flashchromatography and then reverse phase HPLC to give 14.9 mg (19%) of thetitle compound.

LC/MS: m/z 417.0 (M+H)⁺, 0.81 min (ret. time).

¹H NMR (400 MHz, CD₃OD): δ 7.47-7.39 (m, 1H), 7.37-7.22 (m, 2H), 5.80(s, 1H), 5.33 (s, 2H), 4.34-4.22 (m, 2H), 3.91 (d, J=13.1 Hz, 1H),3.82-3.71 (m, 1H), 3.44 (dt, J=3.8, 12.5 Hz, 1H), 3.23 (br. s., 3H),3.08 (d, J=10.5 Hz, 1H), 2.73-2.57 (m, 2H)

E3392-((S)-azetidine-2-carbonyl)-7-((3,4-difluorobenzyl)oxy)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

The title compound was prepared by a procedure similar to that describedfor E333 starting from (2S)-tert-butyl2-(7-((3,4-difluorobenzyl)oxy)-9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2-carbonyl)azetidine-1-carboxylate.

LC/MS: m/z 418.1 (M+H)⁺, 0.59 min (ret. time).

¹H NMR (400 MHz, CD₃OD): δ 7.41-7.31 (m, 1H), 7.27-7.16 (m, 2H),5.39-5.33 (m, 1H), 5.30 (d, J=4.8 Hz, 2H), 4.74 (d, J=9.8 Hz, 1H),4.65-4.48 (m, 1H), 4.26-4.11 (m, 1H), 4.01 (d, J=6.3 Hz, 1H), 3.81-3.68(m, 2H), 3.62-3.45 (m, 2H), 3.25-3.07 (m, 2H), 2.93-2.72 (m, 2H),2.53-2.29 (m, 1H)

E3407-((3,4-Difluorobenzyl)oxy)-2-((S)-pyrrolidine-2-carbonyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

The title compound was prepared by a procedure similar to that describedfor E333 starting from (2S)-tert-butyl2-(7-((3,4-difluorobenzyl)oxy)-9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2-carbonyl)pyrrolidine-1-carboxylate.

LC/MS: m/z 432.1 (M+H)⁺, 0.60 min (ret. time).

¹H NMR (400 MHz, CD₃OD): δ 7.40-7.30 (m, 1H), 7.28-7.17 (m, 2H),5.40-5.28 (m, 3H), 4.73 (d, J=15.1 Hz, 1H), 4.57 (d, J=13.6 Hz, 1H),4.19 (t, J=10.3 Hz, 2H), 4.11-3.89 (m, 2H), 3.81-3.68 (m, 2H), 3.23-3.08(m, 2H), 2.89-2.70 (m, 2H), 2.21 (br. s., 1H), 1.91-1.59 (m, 3H)

E3417-((3,4-Difluorobenzyl)oxy)-2-((2S,4S)-4-fluoropyrrolidine-2-carbonyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

The title compound was prepared by a procedure similar to that describedfor E333 starting from (2S,4S)-tert-butyl2-(7-((3,4-difluorobenzyl)oxy)-9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2-carbonyl)-4-fluoropyrrolidine-1-carboxylate.

LC/MS: m/z 450.0 (M+H)⁺, 0.60 min (ret. time).

¹H NMR (400 MHz, CD₃OD) δ 7.36 (dd, J=7.7, 10.7 Hz, 1H), 7.26 (br. s.,2H), 5.42-5.21 (m, 3H), 5.13 (d, J=10.0 Hz, 1H), 4.74 (d, J=13.1 Hz,1H), 4.57 (d, J=10.0 Hz, 1H), 4.28-3.88 (m, 4H), 3.76 (dd, J=5.8, 11.5Hz, 2H), 3.46-3.34 (m, 1H), 3.21 (d, J=8.0 Hz, 1H), 2.93-2.70 (m, 2H),2.64-2.39 (m, 1H), 2.10-1.83 (m, 1H)

E3427-((3,4-Difluorobenzyl)oxy)-2-((S)-4,4-difluoropyrrolidine-2-carbonyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

The title compound was prepared by a procedure similar to that describedfor E333 starting from (2S)-tert-butyl2-(7-((3,4-difluorobenzyl)oxy)-9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2-carbonyl)-4,4-difluoropyrrolidine-1-carboxylate.

LC/MS: m/z 468.0 (M+H)⁺, 0.61 min (ret. time).

¹H NMR (400 MHz, CD₃OD): δ 7.36 (dd, J=8.0, 10.8 Hz, 1H), 7.28-7.19 (m,2H), 5.40-5.27 (m, 3H), 4.77-4.50 (m, 1H), 4.38-4.27 (m, 1H), 4.23-3.93(m, 3H), 3.80-3.69 (m, 2H), 3.28-3.03 (m, 4H), 2.90-2.72 (m, 1H),2.72-2.49 (m, 1H), 2.38 (dt, J=7.7, 15.5 Hz, 1H)

E3437-((3,4-Difluorobenzyl)oxy)-2-((R)-pyrrolidine-2-carbonyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

The title compound was prepared by a procedure similar to that describedfor E333 starting from (2R)-tert-butyl2-(7-((3,4-difluorobenzyl)oxy)-9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2-carbonyl)pyrrolidine-1-carboxylate.

LC/MS: m/z 432.1 (M+H)⁺, 0.60 min (ret. time).

¹H NMR (400 MHz, CD₃OD): δ 7.41-7.32 (m, 1H), 7.28-7.15 (m, 2H),5.40-5.26 (m, 3H), 4.78-4.50 (m, 1H), 4.26-3.89 (m, 4H), 3.81-3.69 (m,2H), 3.27-3.09 (m, 3H), 2.90-2.71 (m, 2H), 2.20 (d, J=4.5 Hz, 1H),1.93-1.56 (m, 3H)

E3442-(1-Aminocyclobutanecarbonyl)-7-((3,4-difluorobenzyl)oxy)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

The title compound was prepared by a procedure similar to that describedfor E333 starting from tert-butyl(1-(7-((3,4-difluorobenzyl)oxy)-9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2-carbonyl)cyclobutyl)carbamate.

LC/MS: m/z 432.1 (M+H)⁺, 0.62 min (ret. time).

¹H NMR (400 MHz, CD₃OD) δ 7.36 (dd, J=7.9, 10.7 Hz, 1H), 7.28-7.15 (m,2H), 5.42-5.27 (m, 3H), 4.53 (br. s., 1H), 4.31-3.92 (m, 3H), 3.81-3.67(m, 2H), 3.13 (br. s., 2H), 2.66 (s, 3H), 2.01 (br. s., 3H), 1.76-1.58(m, 1H)

E3452-(4-Aminotetrahydro-2H-pyran-4-carbonyl)-7-((3,4-difluorobenzyl)oxy)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

The title compound was prepared by a procedure similar to that describedfor E333 starting from tert-butyl(4-(7-((3,4-difluorobenzyl)oxy)-9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2-carbonyl)tetrahydro-2H-pyran-4-yl)carbamate.

LC/MS: m/z 462.1 (M+H)⁺, 0.60 min (ret. time).

¹H NMR (400 MHz, CD₃OD): δ 7.36 (dd, J=7.8, 10.8 Hz, 1H), 7.29-7.13 (m,2H), 5.38-5.27 (m, 3H), 5.05 (br. s., 1H), 4.23-4.13 (m, 1H), 4.07 (d,J=4.5 Hz, 1H), 3.85-3.66 (m, 6H), 3.28-3.19 (m, 2H), 3.02-2.84 (m, 2H),2.17 (d, J=7.0 Hz, 2H), 1.62 (d, J=3.3 Hz, 2H)

E3467-((3,4-Difluorobenzyl)oxy)-2-(2-(dimethylamino)acetyl)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

The title compound was prepared by a procedure similar to that describedfor E337 starting from 2-(dimethylamino)acetic acid.

LC/MS: m/z 420.1 (M+H)⁺ 0.55 min (ret. time).

¹H NMR (400 MHz, CD₃CN) δ 7.38-7.17 (m, 3H), 5.27 (s, 2H), 5.10 (s, 1H),4.66-4.38 (m, 1H), 4.34-4.09 (m, 1H), 4.09-3.78 (m, 2H), 3.60 (s, 2H),3.24-2.95 (m, 4H), 2.72-2.52 (m, 1H), 2.21 (s, 6H)

E3472-(1-Aminocyclohexanecarbonyl)-7-((3,4-difluorobenzyl)oxy)-3,4,11,11a-tetrahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-9(2H)-one

The title compound was prepared by a procedure similar to that describedfor E333 starting from tert-butyl(1-(7-((3,4-difluorobenzyl)oxy)-9-oxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-2-carbonyl)cyclohexyl)carbamate.

LC/MS: m/z 460.1 (M+H)⁺, 0.63 min (ret. time).

¹H NMR (400 MHz, CD₃CN): δ 7.40-7.16 (m, 3H), 5.26 (s, 2H), 5.09 (s,3H), 4.07-3.98 (m, 1H), 3.96-3.85 (m, 1H), 3.60 (s, 3H), 3.20-3.06 (m,1H), 2.88-2.70 (m, 2H), 1.65-1.40 (m, 8H), 1.37-1.25 (m, 1H)

E3487-((2,3-Difluorobenzyl)oxy)-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione

To a solution of7-chloro-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione(34 mg, 0.141 mmol) and (2,3-difluorophenyl)methanol (30.5 mg, 0.212mmol) in DMF (4 mL) at 23° C. was added sodium hydride (16.95 mg, 0.424mmol). The mixture was stirred at 23° C. for 40 minutes and thenquenched with aq. NH₄Cl. The mixture was concentrated and EA and waterwas added. The layers were separated and the water layer was extractedwith EA for 6 times. The combined organic lyer was concentrated and thecrude was purified using CombiFlash Rf 200 with a gradient of 100% DCMto 10% MeOH in DCM then neutral Gilson at a gradient of 10% to 85%water/MeCN to give 5 mg of the title compound.

LC/MS: m/z 349.0 (M+H)⁺, 0.57 min(ret. time).

¹H NMR (400 MHz, DMSO-d₆): δ 3.24-3.43 (m, 2H) 3.71 (dd, J=11.54, 6.02Hz, 1H) 3.81 (d, J=17.57 Hz, 1H) 4.01-4.27 (m, 3H) 5.36 (s, 3H)7.19-7.36 (m, 2H) 7.44 (d, J=8.78 Hz, 1H) 8.17 (br. s., 1H)

E349 and E3505-(((3,9-Dioxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)-2-fluorobenzonitrile(E349)

5-((2-cyano-4-(((3,9-dioxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)phenoxy)methyl)-2-fluorobenzonitrile(E350)

To a solution of7-chloro-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione(318 mg, 1.321 mmol) and 2-fluoro-5-(hydroxymethyl)benzonitrile (200 mg,1.321 mmol) in DMSO (10 mL) was added sodium hydride (132 mg, 3.30 mmol)at room temperature and the mixture was stirred for 60 minutes. Thenwater was added to quench the reaction and the mixture was concentrated.Water and EA were added and the water layer was extracted with EA for 5times. The combined organic layer was concentrated and the crude waspurified using CombiFlash Rf 200 with a gradient of 100% DCM to 10% MeOHin DCM and then purified again using neutral Gilson at a gradient of 10%to 80% water/MeCN to give the title compound5-(((3,9-Dioxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)-2-fluorobenzonitrile(13 mg) and5-((2-cyano-4-(((3,9-dioxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)phenoxy)methyl)-2-fluorobenzonitrile (3 mg).

E349

LC/MS: m/z 356.0 (M+H)⁺, 0.51 min(ret. time).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.22-3.42 (m, 4H) 3.71 (dd, J=11.54,6.02 Hz, 1H) 3.82 (d, J=17.57 Hz, 1H) 4.02-4.31 (m, 3H) 7.56 (t, J=9.03Hz, 1H) 7.83 (t, J=6.90 Hz, 1H) 7.96 (d, J=6.27 Hz, 1H) 8.16 (d, J=3.76Hz, 1H)

E350

LC/MS: m/z 387.1 (M+H)⁺, 0.76 min(ret. time).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.23-3.43 (m, 2H) 3.64-3.86 (m, 2H)4.02-4.27 (m, 3H) 5.23 (s, 2H) 5.33 (s, 3H) 7.36 (d, J=8.78 Hz, 1H) 7.63(t, J=8.91 Hz, 1H) 7.72 (d, J=8.53 Hz, 1H) 7.80 (s, 1H) 7.91 (br. s.,1H) 8.06 (d, J=6.27 Hz, 1H) 8.15 (br. s., 1H)

E3517-((3,5-Difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)benzyl)oxy)-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione

The title compound was prepared by a procedure similar to that describedfor E348 starting from7-chloro-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dioneand(3,5-difluoro-4-((2-(trifluoromethyl)pyridin-4-yl)oxy)phenyl)methanol.

LC/MS: m/z 510.0 (M+H)⁺, 0.81 min (ret. time).

¹H NMR (400 MHz, CD₃OD): δ ppm 3.40-3.62 (m, 2H) 3.86 (dd, J=11.29, 6.02Hz, 1H) 4.00 (d, J=17.82 Hz, 1H) 4.18-4.41 (m, 3H) 5.42 (s, 3H) 7.18 (d,J=5.02 Hz, 1H) 7.34 (d, J=8.78 Hz, 2H) 7.44 (s, 1H) 8.63 (d, J=5.77 Hz,1H)

E3527-((3,5-Difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione

The title compound was prepared by a procedure similar to that describedfor E348 starting from7-chloro-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dioneand(3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol.

LC/MS: m/z 510.0 (M+H)⁺, 0.80 min (ret. time).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.24-3.46 (m, 3H) 3.72 (dd, J=11.80,6.27 Hz, 1H) 3.83 (d, J=17.57 Hz, 1H) 4.02-4.30 (m, 3H) 5.34 (s, 2H)5.40 (s, 1H) 7.41 (d, J=9.29 Hz, 2H) 7.94 (br. s., 1H) 8.18 (br. s., 1H)8.78 (d, J=15.56 Hz, 1H)

E3537-((3,4-Difluorobenzyl)amino)-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione

A solution of7-chloro-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione(98 mg, 0.407 mmol), (3,4-difluorophenyl)methanamine (0.053 mL, 0.448mmol) and TEA (0.114 mL, 0.814 mmol) in DMSO (3 mL) in a microwave vialwas heated to 160° C. using Microwave for 30 minutes. The crude productwas purified using neutral Gilson at a gradient of 10% to 80% water/MeCNto give the title compound (75 mg).

LC/MS: m/z 347.9 (M+H)⁺, 0.50 min (ret. time).

¹H NMR (400 MHz, CD₃OD): δ 3.41 (dd, J=12.17, 10.16 Hz, 1H) 3.48-3.59(m, 1H) 3.74 (d, J=5.02 Hz, 1H) 3.86-3.97 (m, 1H) 4.03-4.27 (m, 3H) 4.54(br. s., 2H) 5.04 (s, 1H) 7.02-7.31 (m, 3H)

E3545-(((3,9-dioxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)amino)methyl)-2-fluorobenzonitrile,Trifluoroacetic Acid Salt

The title compound was prepared by a procedure similar to that describedfor E353 starting from7-chloro-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dioneand 5-(aminomethyl)-2-fluorobenzonitrile.

LC/MS: m/z 355.0 (M+H)⁺, 0.53 min (ret. time).

¹H NMR (400 MHz, CD₃OD): δ ppm 3.40-3.66 (m, 2H) 3.89 (dd, J=11.29, 6.53Hz, 1H) 4.07 (d, J=17.82 Hz, 1H) 4.25-4.39 (m, 2H) 4.45 (br. s., 1H)4.62 (s, 2H) 5.35 (m, 1H) 7.42 (t, J=8.78 Hz, 1H) 7.69-7.85 (m, 1H)

E3557-((2,3-Difluorobenzyl)amino)-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione

The title compound was prepared by a procedure similar to that describedfor E353 starting from7-chloro-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dioneand (2,3-difluorophenyl)methanamine.

LC/MS: m/z 348.1 (M+H)⁺, 0.49 min (ret. time).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.17-3.44 (m, 4H) 3.57 (dd, J=11.04,6.27 Hz, 1H) 3.71-3.83 (m, 1H) 3.86-4.02 (m, 2H) 4.02-4.14 (m, 1H) 4.95(br. s., 1H) 7.07-7.23 (m, 2H) 7.24-7.36 (m, 1H) 7.60 (br. s., 1H) 8.14(d, J=4.77 Hz, 1H)

E3567-((3,4-difluorobenzyl)oxy)-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione

The title compound was prepared by a procedure similar to that describedfor E348 starting from7-chloro-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dioneand (3,4-difluorophenyl)methanol.

LC/MS: m/z 349.0 (M+H)⁺, 0.58 min (ret. time).

¹H NMR (400 MHz, DMSO-d₆): δ 3.22-3.44 (m, 3H) 3.64-3.87 (m, 2H)3.99-4.29 (m, 3H) 5.26 (s, 2H) 5.35 (s, 1H) 7.27 (br. s., 1H) 7.36-7.55(m, 2H) 8.16 (d, J=3.76 Hz, 1H).

E3572-Fluoro-5-(((2-methyl-3,9-dioxo-2,3,4,9,11,11a-hexahydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)oxy)methyl)benzonitrile

The title compound was prepared by a procedure similar to that describedfor E348 starting from7-chloro-2-methyl-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dioneand 2-fluoro-5-(hydroxymethyl).

LC/MS: m/z 370.0 (M+H)⁺, 0.59 min (ret. time).

¹H NMR (400 MHz, DMSO-d₆): δ 2.89 (s, 3H) 3.38-3.60 (m, 2H) 3.76 (d,J=5.52 Hz, 1H) 3.88 (d, J=17.57 Hz, 1H) 4.04-4.24 (m, 2H) 4.26-4.40 (m,1H) 5.30 (s, 2H) 5.40 (s, 1H) 6.52 (s, 1H) 7.52-7.61 (m, 1H) 7.83 (br.s., 1H) 7.96 (d, J=4.52 Hz, 1H).

E3587-((3,4-Difluorobenzyl)oxy)-2-(2,2,2-trifluoroethyl)-11,11a-dihydro-1Hpyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione

To a stirred suspension of7-((3,4-difluorobenzyl)oxy)-11,11a-dihydro-1Hpyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione(83 mg, 0.238 mmol) in THF (5 mL) and NMP (3 mL) at 0° C. was addedlithium bis(trimethylsilyl)amide (1.0 M in THF) (0.274 mmol) dropwise,the resulting mixture was stirred at 0° C. for 15 min, then2,2,2-trifluoroethyl trifluoromethanesulfonate (0.039 mL, 0.274 mmol)was added dropwise. The mixture was allowed to warm to RT and stirredfor 1 hour. The resulting mixture was partitioned between 20 mL aq.NaHCO₃ and EA (30 mL). The combined organic layer was concentrated andthe crude was purified using CombiFlash Rf 200 with a gradient of 100%DCM to 10% MeOH in DCM and then purified again using neutral Gilson at agradient of 10% to 90% water/MeCN to give the title compound (46 mg) asa white solid.

LC/MS: m/z 431.0 (M+H)⁺, 0.75 min (ret. time).

¹H NMR (400 MHz, DMSO-d₆): δ 3.58-3.71 (m, 2H) 3.76 (dd, J=11.80, 6.02Hz, 1H) 4.02 (d, J=17.82 Hz, 1H) 4.07-4.22 (m, 2H) 4.27-4.41 (m, 3H)5.26 (s, 2H) 5.40 (s, 1H) 7.27 (br. s., 1H) 7.37-7.53 (m, 2H)

E3597-((3,4-Difluorobenzyl)oxy)-2-methyl-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione

To a solution of7-((3,4-difluorobenzyl)oxy)-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione (71 mg, 0.204 mmol) and 18-crown-6 (2.55 mg, 10.19 μmol)in THF (10 mL) and DMSO (2 mL) at 0° C. was added sodium hydride (16.31mg, 0.408 mmol). The reaction mixture was then stirred for 20 minutes atRT, then at 0° C., iodomethane (0.020 mL, 0.326 mmol) was added. Themixture was stirred at RT for two hours. Water was added to quench thereaction. The mixture was then concentrated and the crude was purifiedusing CombiFlash Rf 200 with a gradient of 100% DCM to 20% MeOH in DCM,the product came out about 12% MeOH in DCM and then purified again usingneutral Gilson at a gradient of 10% to 85% water/MeCN to give 58 mg ofthe title compound as a white solid.

LC/MS: m/z 363.0 (M+H)⁺, 0.61 min (ret. time).

¹H NMR (400 MHz, DMSO-d₆): δ 2.88 (s, 3H) 3.38-3.58 (m, 2H) 3.73 (dd,J=11.54, 5.77 Hz, 1H) 3.87 (d, J=17.32 Hz, 1H) 4.09 (dd, J=11.54, 9.03Hz, 1H) 4.18 (d, J=17.57 Hz, 1H) 4.31 (dd, J=9.29, 4.77 Hz, 1H) 5.26 (s,2H) 5.38 (s, 1H) 7.26 (br. s., 1H) 7.36-7.53 (m, 1H)

E3607-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-2-methyl-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dione,Trifluoroacetic Acid Salt

The title compound was prepared by a procedure similar to that describedfor E348 starting from7-chloro-2-methyl-11,11a-dihydro-1H-pyrazino[1′,2′:3,4]imidazo[1,2-c]pyrimidine-3,9(2H,4H)-dioneand (3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)phenyl)methanol.

LC/MS: m/z 470.0 (M+H)⁺, 0.60 min (ret. time).

¹H NMR (400 MHz, DMSO-d₆): δ 2.47 (s, 3H) 2.90 (s, 3H) 3.42-3.53 (m, 1H)3.53-3.66 (m, 1H) 3.83 (dd, J=11.80, 5.77 Hz, 1H) 4.00 (d, J=17.57 Hz,1H) 4.09-4.24 (m, 1H) 4.35 (d, J=17.57 Hz, 2H) 5.35 (s, 2H) 5.76 (s, 1H)7.01 (s, 1H) 7.14 (s, 1H) 7.26 (s, 1H) 7.29-7.37 (m, 1H) 7.42 (d, J=8.78Hz, 2H) 8.34 (d, J=2.76 Hz, 1H)

E3617-((2,3-Difluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one

The title compound was prepared by a procedure similar to that describedfor E348 starting from7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-oneand (2,3-difluorophenyl)methanol.

LC/MS: m/z 352 (M+H)⁺, 0.706 min (ret. time).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.54-2.61 (m, 1H) 2.66-2.83 (m, 3H) 3.17(t, J=12.55 Hz, 1H) 3.52-3.59 (m, 1H) 3.95-4.15 (m, 3H) 5.34 (br. s.,1H) 5.35 (br. s., 2H) 7.19-7.28 (m, 1H) 7.28-7.35 (m, 1H) 7.38-7.49 (m,1H).

E362 and E3637-((2,3-Difluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one 2-oxide (E362)

7-((2,3-Difluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one 2,2-dioxide (E363)

To a solution of7-((2,3-difluorobenzyl)oxy)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one (142 mg, 0.40 mmol, 1.0 equiv) in THF (3 mL) and water(1 mL) was added oxone (248 mg, 0.40 mmol, 1.0 equiv) and the reactionwas stirred at rt for 1 h. The mixture was quenched with saturatedNaHCO₃ dropwise and then concentrated. The residue was re-dissolved insaturated NaHCO₃ (3 mL) and water (15 mL), and 10% MeOH in DCM (20 mL).The mixture was filtered through celite. The celite cake was repeatedlywashed with 10% MeOH in DCM (20 mL). The combined filtrate was phaseseparated. The aqueous portion was back extracted with 10% MeOH in DCM(20 mL). The combined organic was concentrated and purified by GilsonHPLC (Sunfire 5 μm C18 OBD 19×100 mm, 10%˜90% CH₃CN/H₂O (0.1% TFA)preparatory column) to give the title compound E362 (70 mg) as a whitesolid and E363 (152 mg) as a white solid.

E362: LC/MS: m/z 367.9 (M+H)⁺, 0.61 min (ret. time).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.75-2.85 (m, 1H) 2.88-2.96 (m, 2H) 3.11(d, J=14.05 Hz, 1H) 3.67 (dd, J=11.54, 6.53 Hz, 1H) 3.71-3.80 (m, 1H)3.81-3.89 (m, 1H) 4.12 (t, J=10.29 Hz, 1H) 4.50-4.62 (m, 1H) 5.30-5.40(m, 2H) 5.45 (s, 1H) 7.18-7.27 (m, 1H) 7.27-7.34 (m, 1H) 7.37-7.48 (m,1H).

E363: LC/MS: m/z 383.9 (M+H)⁺, 0.66 min (ret. time).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.22-3.34 (m, 3H) 3.41 (d, J=6.02 Hz,1H) 3.49-3.58 (m, 1H) 3.72 (dd, J=11.80, 6.02 Hz, 1H) 4.07-4.16 (m, 1H)4.20 (d, J=14.05 Hz, 1H) 4.33-4.44 (m, 1H) 5.31-5.42 (m, 2H) 5.49 (s,1H) 7.20-7.28 (m, 1H) 7.29-7.36 (m, 1H) 7.44 (q, J=9.03 Hz, 1H).

The following compounds E364-E373 listed in Table 5 were prepared by aprocedure similar to that described for E362 and E363 starting from therequisite benzyl alcohols and intermediates:

TABLE 5 ¹HNMR Ex # Name Structure LCMS (400 MHz) E364 2-Fluoro-5-(((9-oxo- 1,3,4,9,11,11a- hexahydro- pyrimido [6′,1′:2,3] imidazo[5,1-c][1,4]thiazin- 7-yl)oxy) methyl) benzonitrile

m/z 359 (M + H)⁺, 0.689 min (ret. time) DMSO-d6: δ ppm 2.55-2.63 (m, 1H) 2.65-2.85 (m, 3 H) 3.12- 3.25 (m, 1 H) 3.51-3.60 (m, 1 H) 3.95-4.16(m, 3 H) 5.29 (s, 2 H) 5.35 (s, 1 H) 7.56 (t, J = 9.03 Hz, 1 H) 7.78-7.87 (m, 1 H) 7.96 (dd, J = 6.27, 2.26 Hz, 1 H). E365 5-((2- Cyano-4-(((9-oxo- 1,3,4,9,11,11a- hexahydro- pyrimido [6′,1′:2,3] imidazo[5,1-c][1,4] thiazin-7- yl)oxy)methyl) phenoxy) methyl)-2- fluoro-benzonitrile

m/z 490 (M + H)⁺, 0.854 min (ret. time). DMSO-d6: δ ppm 2.54-2.62 (m, 1H) 2.66-2.84 (m, 3 H) 3.11- 3.23 (m, 1 H) 3.55 (dd, J = 10.79, 6.53 Hz,1 H) 3.95- 4.15 (m, 3 H) 5.22 (s, 2 H) 5.31 (s, 1 H) 5.33 (s, 2 H) 7.36(d, J = 8.78 Hz, 1 H) 7.63 (t, J = 9.03 Hz, 1 H) 7.72 (dd, J = 8.66,2.13 Hz, 1 H) 7.80 (d, J = 2.01 Hz, 1 H) 7.91 (ddd, J = 8.47, 5.58, 2.26Hz, 1 H) 8.06 (dd, J = 6.27, 2.26 Hz, 1 H). E366 2-Fluoro- 5-(((2-oxido-9-oxo- 1,3,4,9,11,11a- hexahydro- pyrimido [6′,1′:2,3]imidazo[5,1- c][1,4] thiazin-7- yl)oxy)methyl) benzonitrile

m/z 374.9 (M + H)⁺, 0.56 min (ret. time). DMSO-d6, selected signals: δppm 2.75- 2.87 (m, 1 H) 2.87-2.97 (m, 1 H) 3.07-3.15 (m, 2 H) 3.67 (dd,J = 11.54, 6.53 Hz, 1 H) 3.71-3.77 (m, 1 H) 3.80 (d, J = 9.54 Hz, 1 H)4.08-4.18 (m, 1 H) 4.56 (d, J = 8.78 Hz, 1 H) 5.29 (s, 2 H) 5.43 (s, 1H) 7.53 (t, J = 9.03 Hz, 1 H) 7.81 (t, J = 5.90 Hz, 1 H) 7.94 (d, J =6.27 Hz, 1 H). E367 5-(((2,2- Dioxido- 9-oxo- 1,3,4,9,11,11a- hexahydro-pyrimido [6′,1′:2,3] imidazo[5,1- c][1,4]thiazin- 7-yl)oxy) methyl)-2-fluoro- benzonitrile

m/z 390.9 (M + H)⁺, 0.65 min (ret. time) DMSO-d6: δ ppm 3.26 (d, J =5.02 Hz, 2 H) 3.40- 3.49 (m, 2 H) 3.49-3.57 (m, 1 H) 3.71 (dd, J =11.54, 6.02 Hz, 1 H) 4.09- 4.16 (m, 1 H) 4.20 (d, J = 14.31 Hz, 1 H)4.37 (br. s., 1 H) 5.31 (s, 2 H) 5.51 (s, 1 H) 7.57 (t, J = 9.03 Hz, 1H) 7.79- 7.87 (m, 1 H) 7.96 (d, J = 6.27 Hz, 1 H). E368 7-((3,5-Difluoro- 4-((2- (trifluoromethyl) pyridin-4- yl)oxy)benzyl) oxy)3,4,11,11a- tetrahydro pyrimido [6′,1′:2,3] imidazo[5,1- c][1,4]thiazin-9(1H)-one

m/z 513 (M + H)⁺, 0.937 min (ret. time DMSO-d6: δ ppm 2.55-2.64 (m, 1 H)2.66-2.85 (m, 3 H) 3.20 (t, J = 11.67 Hz, 1 H) 3.55-3.59 (m, 1 H)3.98-4.17 (m, 3 H) 5.34 (s, 2 H) 5.39 (s, 1 H) 7.32 (d, J = 4.02 Hz, 1H) 7.44 (d, J = 9.03 Hz, 2 H) 7.67 (s, 1 H) 8.69 (d, J = 5.77 Hz, 1 H).E369 7-((3,5- Difluoro-4-((2- (trifluoromethyl) pyridin-4-yl)oxy)benzyl) oxy)-3,4,11,11a- tetrahydro pyrimido [6′,1′:2,3]imidazo[5,1- c][1,4] thiazin-9(1H)- one 2-oxide

m/z 528.9 (M + H)⁺, 0.81 min (ret. time). DMSO-d6: δ ppm 3.23-3.28 (m, 2H) 3.40-3.47 (m, 2 H) 3.47- 3.57 (m, 1 H) 3.71 (dd, J = 11.67, 5.90 Hz,1 H) 4.08- 4.17 (m, 1 H) 4.21 (d, J = 14.30 Hz, 1 H) 4.38 (d, J = 8.03Hz, 1 H) 5.34 (s, 2 H) 5.53 (s, 1 H) 7.39 (d, J = 9.03 Hz, 2 H) 7.91(br. s., 1 H) 8.74 (s, 1 H) 8.79 (s, 1 H). E370 7-((3,5- Difluoro-4-((2-(trifluoromethyl) pyridin-4- yl)oxy)benzyl) oxy)-3,4,11,11a- tetrahydropyrimido [6′,1′:2,3] imidazo[5,1- c][1,4] thiazin-9(1H)- one-2,2-dioxide

m/z 544.9 (M + H)⁺, 0.90 min (ret. time). DMSO-d6: δ ppm 3.23-3.28 (m, 2H) 3.40-3.47 (m, 2 H) 3.47- 3.57 (m, 1 H) 3.71 (dd, J = 11.67, 5.90 Hz,1 H) 4.08- 4.17 (m, 1 H) 4.21 (d, J = 14.30 Hz, 1 H) 4.38 (d, J = 8.03Hz, 1 H) 5.34 (s, 2 H) 5.53 (s, 1 H) 7.39 (d, J = 9.03 Hz, 2 H) 7.91(br. s., 1 H) 8.74 (s, 1 H) 8.79 (s, 1 H). E371 7-((3,5- Difluoro-4-((5-(trifluoromethyl) pyridin-3- yl)oxy)benzyl) oxy)-3,4,11,11a- tetrahydropyrimido [6′,1′:2,3] imidazo[5,1-c] [1,4]thiazin- 9(1H)-one

m/z 513 (M + H)⁺, 0.924 min (ret. time). DMSO-d6: δ ppm 3.23-3.28 (m, 2H) 3.40-3.47 (m, 2 H) 3.47- 3.57 (m, 1 H) 3.71 (dd, J = 11.67, 5.90 Hz,1 H) 4.08- 4.17 (m, 1 H) 4.21 (d, J = 14.30 Hz, 1 H) 4.38 (d, J = 8.03Hz, 1 H) 5.34 (s, 2 H) 5.53 (s, 1 H) 7.39 (d, J = 9.03 Hz, 2 H) 7.91(br. s., 1 H) 8.74 (s, 1 H) 8.79 (s, 1 H). E372 7-((3,5- Difluoro-4-((5-(trifluoromethyl) pyridin-3- yl)oxy)benzyl) oxy)-3,4,11,11a- tetrahydropyrimido [6′,1′:2,3] imidazo[5,1- c][1,4]thiazin- 9(1H)- one 2-oxide

m/z 528.9 (M + H)⁺, 0.81 min (ret. time). DMSO-d6: δ ppm 3.23-3.28 (m, 2H) 3.40-3.47 (m, 2 H) 3.47- 3.57 (m, 1 H) 3.71 (dd, J = 11.67, 5.90 Hz,1 H) 4.08- 4.17 (m, 1 H) 4.21 (d, J = 14.30 Hz, 1 H) 4.38 (d, J = 8.03Hz, 1 H) 5.34 (s, 2 H) 5.53 (s, 1 H) 7.39 (d, J = 9.03 Hz, 2 H) 7.91(br. s., 1 H) 8.74 (s, 1 H) 8.79 (s, 1 H). E373 7-((3,5- Difluoro-4-((5-(trifluoromethyl) pyridin-3- yl)oxy)benzyl) oxy)-3,4,11,11a- tetrahydropyrimido [6′,1′:2,3] imidazo[5,1-c] [1,4]thiazin- 9(1H)-one 2,2-dioxide

m/z 544.9 (M + H)⁺, 0.89 min (ret. time). DMSO-d6: δ ppm 3.23-3.28 (m, 2H) 3.40-3.47 (m, 2 H) 3.47- 3.57 (m, 1 H) 3.71 (dd, J = 11.67, 5.90 Hz,1 H) 4.08- 4.17 (m, 1 H) 4.21 (d, J = 14.30 Hz, 1 H) 4.38 (d, J = 8.03Hz, 1 H) 5.34 (s, 2 H) 5.53 (s, 1 H) 7.39 (d, J = 9.03 Hz, 2 H) 7.91(br. s., 1 H) 8.74 (s, 1 H) 8.79 (s, 1 H).

E3747-((3,4-Difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one

A mixture of7-chloro-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one(109 mg, 0.45 mmol, 1 equiv) and (3,4-difluorobenzylamine (77 mg, 0.54mmol, 1.2 equiv) and K₂CO₃ (185 mg, 1.34 mmol, 3 equiv) in (2 mL) washeated at 100° C. for 16 hrs. The mixture was acidified with 0.5 mL of6N HCl and filtered. The filtrate was concentrated and purified on aGilson HPLC (Sunfire 5 μm C18 OBD 19×100 mm, 10%-90% CH₃CN/H₂O (0.1%TFA)) to give the title compound (52 mg) as a white solid.

LC/MS: m/z 350.9 (M+H)⁺, 0.67 min (ret. time).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.53-2.61 (m, 1H) 2.65-2.77 (m, 3H)3.08-3.14 (m, 1H) 3.41 (t, J=9.29 Hz, 1H) 3.89 (br. s., 1H) 3.96-4.04(m, 1H) 4.06 (q, J=5.27 Hz, 1H) 4.42 (br. s., 2H) 4.90 (br. s., 1H) 7.11(br. s., 1H) 7.24-7.43 (m, 2H) 7.54 (br. s., 1H).

E3757-((3,4-Difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one2-oxide

To a solution of7-((3,4-Difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one(97 mg, 0.28 mmol, 1.0 equiv) in 3 mL of THF, 0.5 mL of 1N HCl and 0.5mL of water at rt was added oxone (42 mg) in one portion. The mixturewas stirred at room temperature for 3.5 hrs and concentrated to removeTHF. The resulting slurry was basified with saturated NaHCO₃ solution topH=8/9. The mixture was diluted with water (8 mL) and 10% MeOH in DCM(30 mL), and filtered through celite. The filtrate was phase separatedand the aqueous was extracted with 10% MeOH in DCM (3×10 mL). Thecombined organic layer was dried over Na₂SO₄, filtered, andconcentrated. The crude was purified by Combiflash system (24 g silicagel cartridge) to give 83 mg of the title compound as diastereomers (3:7roughly).

LC/MS: m/z 366.9 (M+H)⁺, 0.54 min (ret. time).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 2.58-2.73 (m, 1H) 2.74-2.86 (m, 2H)2.86-2.95 (m, 1H) 3.09 (d, J=13.55 Hz, 1H) 3.53 (dd, J=11.17, 6.65 Hz,1H) 3.57-3.65 (m, 1H) 3.65-3.77 (m, 1H) 3.92-4.09 (m, 2H) 4.32-4.54 (m,2H) 4.99 (br. s., 1H) 7.12 (br. s., 1H) 7.24-7.34 (m, 2H) 7.34-7.42 (m,1H) 7.58 (br. s., 1H).

E3767-((3,4-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one2,2-dioxide

To a cloudy mixture of7-((3,4-difluorobenzyl)amino)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one(250 mg, 0.71 mmol, 1.0 equiv) in THF (6 mL) and water (2 mL) at rt wasadded oxone (136 mg) in one portion. The reaction was monitored by LCMSevery 0.5-1.0 h, followed by addition of incremental amounts of oxone(181 and 50 mg). After 4.5 h at rt, the mixture was concentrated toremove THF. The resulting slurry was basified with saturated NaHCO₃solution to pH=8/9. The mixture was diluted with water (15 mL) and 10%MeOH in DCM (30 mL), and filtered through celite. The filtrate was phaseseparated and the aqueous layer was extracted with 10% MeOH in DCM (3×10mL). The combined organic was dried over Na₂SO₄, filtered, andconcentrated. The crude was purified by Gilson HPLC (Sunfire 5 μm C18OBD 19×100 mm, 10% 80% CH₃CN/H₂O (0.1% TFA)) and then Redi-Sep 12 gsilica gel cartridge to give the title compound (34 mg) as a whitesolid.

LC/MS: m/z 382.9 (M+H)⁺, 0.50 min (ret. time).

¹H NMR (400 MHz, DMSO-d₆): δ ppm 3.18-3.27 (m, 2H) 3.34-3.46 (m, 3H)3.57 (dd, J=11.29, 6.53 Hz, 1H) 3.91-4.05 (m, 2H) 4.17-4.27 (m, 1H) 4.44(br. s., 2H) 5.01 (br. s., 1H) 7.12 (br. s., 1H) 7.24-7.33 (m, 1H) 7.37(dt, J=10.79, 8.53 Hz, 1H) 7.62 (br. s., 1H).

The following compounds E377-E379 listed in Table 6 were prepared by aprocedure similar to that described for E375 and E376 starting from fromthe requisite benzyl amines and intermediates:

TABLE 6 Ex # Name Structure LCMS ¹HNMR (400 MHz) E377 7-((2,3-Difluorobenzyl) amino)-3,4,11,11a- tetrahydro pyrimido[6′,1′:2,3]imidazo[5,1- c][1,4]thiazin- 9(1H)-one

350.9 (M + H)⁺, 0.64 min (ret. time). DMSO-d6: δ ppm 2.56 (d, J = 13.30Hz, 1 H) 2.64-2.77 (m, 3 H) 3.06-3.14 (m, 1 H) 3.39 (dd, J = 10.67, 7.91Hz, 1 H) 3.77 (d, J = 13.55 Hz, 1 H) 3.82- 3.92 (m, 1 H) 3.95- 4.03 (m,1 H) 4.52 (br. s., 2 H) 4.92 (br. s., 1 H) 7.08-7.20 (m, 2 H) 7.23-7.35(m, 1 H) 7.49 (br. s., 1 H). E378 7-((2,3- Difluorobenzyl)amino)-3,4,11,11a- tetrahydro pyrimido[6′,1′:2,3] imidazo[5,1-c][1,4]thiazin- 9(1H)- one-2-oxide

m/z 366.9 (M + H)⁺, 0.52 min (ret. time). DMSO-d6, selected signals: δppm 2.87- 2.95 (m, 1 H) 3.03- 3.13 (m, 1 H) 3.53 (dd, J = 11.17, 6.65Hz, 1 H) 3.56-3.63 (m, 1 H) 3.65-3.76 (m, 1 H) 4.00 (dd, J = 11.17, 8.66Hz, 1 H) 4.32- 4.44 (m, 1 H) 4.53 (br. s., 2 H) 5.01 (br. s., 1 H)7.08-7.20 (m, 2 H) 7.25-7.36 (m, 1 H) 7.62 (br. s., 1 H). E379 7-((2,3-Difluorobenzyl) amino)-3,4,11,11a- tetrahydro pyrimido[6′,1′:2,3]imidazo[5,1- c][1,4]thiazin- 9(1H)-one-2,2- dioxide

m/z 382.9 (M + H)⁺, 0.57 min (ret. time). DMSO-d6: δ ppm 3.19- 3.27 (m,2 H) 3.33- 3.46 (m, 3 H) 3.57 (dd, J = 11.29, 6.53 Hz, 1 H) 3.94-4.04(m, 2 H) 4.16-4.27 (m, 1 H) 4.53 (br. s., 2 H) 5.03 (br. s., 1 H)7.07-7.21 (m, 2 H) 7.25-7.36 (m, 1 H) 7.61 (br. s., 1 H).

E3807-(2,3-Difluorophenethyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one

A solution of7-((2,3-difluorophenyl)ethynyl)-3,4,11,11a-tetrahydropyrimido[6′,1′:2,3]imidazo[5,1-c][1,4]thiazin-9(1H)-one(100 mg) in EtOH (30 mL) and of MeOH (70 mL) was treated in the H-Cubeusing a 20% Pd(OH)₂/C cartridge under 90 Bar and was stirred at 55° C.for 9 hrs. The mixture was filtered and concentrated. The crude waspurified by Gilson HPLC (Sunfire 5 μm C18 OBD 19×100 mm, 10%-90%CH₃CN/H₂O (0.1% TFA)) to give the title compound (25 mg) as a lightyellowish oily residue.

LC/MS: m/z 350 (M+H)⁺, 0.610 min (ret. time).

¹H NMR (400 MHz, 1:1 CD₂Cl₂: CD₃OD): δ ppm 2.50-2.61 (m, 1H) 2.67-2.86(m, 5H) 3.00 (t, J=7.65 Hz, 2H) 3.32-3.43 (m, 1H) 3.69-3.71 (m, 1H)3.92-3.95 (m, 1H) 4.13-4.23 (m, 1H) 4.24-4.33 (m, 1H) 5.60 (s, 1H)6.94-7.09 (m, 3H).

E3812-Fluoro-5-((((7R,8aR)-7-hydroxy-1-oxo-1,6,7,8,8a,9-hexahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)benzonitrile

To a solution of(7R,8aR)-7-((tert-Butyldimethylsilyl)oxy)-3-chloro-7,8,8a,9tetrahydropyrrolo[1′,2′:3,4] imidazo[1,2-c]pyrimidin-1(6H)-one (30 mg,0.088 mmol) and 2-fluoro-5-(hydroxymethyl)benzonitrile (13.26 mg, 0.088mmol) in THF (627 μl) was added NaH (8.77 mg, 0.219 mmol). After 40 minat room temperature, the reaction was quenched with MeOH andconcentrated. The crude was purified by reverse-phase HPLC (10-70%CH₃CN:H₂O, 0.1% TFA as modifier) to TBS-protected intermediate as awhite solid (LC/MS: m/z 457.2 (M+H)⁺, 1.10 min (ret. time)). To thisintermediate in THF (850 μl) at 0° C. was added added TBAF (1.0 M inTHF) (44.4 mg, 0.170 mmol) dropwise and the reaction was stirred for 20min. The mixture was then diluted with saturated NH₄Cl and extractedEtOAc for three times. The combined organic layer was dried over Na₂SO₄,filtered and concentrated. The crude was purified by reverse-phase HPLC(10-60% CH₃CN:H₂O, 0.1% TFA as modifier) and then 4 g CombiFlash column(0-5% MeOH: DCM) to give the title compound as a white solid.

LC/MS: m/z 343.0 (M+H)⁺, 0.57 min (ret. time).

¹H NMR (400 MHz, CD₃OD): δ ppm 1.72 (d, J=13.30 Hz, 1H) 2.30-2.44 (m,1H) 3.36 (d, J=4.02 Hz, 1H) 3.40-3.49 (m, 1H) 3.91-4.01 (m, 1H)4.21-4.34 (m, 2H) 4.48 (br. s., 1H) 5.35 (d, J=6.78 Hz, 2H) 5.41 (s, 1H)7.35 (t, J=8.91 Hz, 1H) 7.75-7.82 (m, 1H) 7.85 (d, J=5.77 Hz, 1H)

The following compounds E382-E385 listed in Table 7 were prepared by aprocedure similar to that described for E381 starting from the requisite4-hydroxyproline and benzyl alcohol:

TABLE 7 Ex # Name Structure LCMS ¹H NMR (400 MHz) E382 2-Fluoro-5-((((7S,8aS)-7- hydroxy-1-oxo- 1,6,7,8,8a,9- hexahydro pyrrolo[1′,2′:3,4]imidazo[1,2- c]pyrimidin-3- yl)oxy)methyl) benzonitrile

m/z 343.0 (M + H)⁺, 0.57 min (ret. time) CD₃OD: δ ppm 1.74 (d, J = 13.30Hz, 1 H) 2.34- 2.45 (m, 1 H) 3.39 (d, J = 4.02 Hz, 1 H) 3.43- 3.51 (m, 1H) 3.99 (d, J = 6.53 Hz, 1 H) 4.24- 4.38 (m, 2 H) 4.50 (br. s., 1 H)5.37 (d, J = 6.78 Hz, 2 H) 5.43 (s, 1 H) 7.37 (t, J = 8.78 Hz, 1 H)7.78-7.85 (m, 1 H) 7.87 (d, J = 5.52 Hz, 1 H) E383 (7S,8aS)-3-((3,5-Difluoro-4- ((2-(trifluoromethyl) pyridin-4- yl)oxy)benzyl)oxy)-7-hydroxy- 7,8,8a,9- tetrahydro pyrrolo[1′,2′:3,4] imidazo[1,2-

m/z 497.0 (M + H)⁺, 0.86 min (ret. time) CD₃OD: δ ppm 1.73 (d, J = 13.55Hz, 1 H) 2.31- 2.46 (m, 1 H) 3.33-3.40 (m, 1 H) 3.42-3.51 (m, 1 H) 3.98(d, J = 6.53 Hz, 1 H) 4.29 (q, J = 10.04 Hz, 2 H) 4.49 c]pyrimidin- (br.s., 1 H) 5.39 1(6H)-one (d, J = 6.02 Hz, 2 H) 5.46 (s, 1 H) 7.16 (d, J =4.77 Hz, 1 H) 7.32 (d, J = 8.78 Hz, 2 H) 7.42 (s, 1 H) 8.61 (d, J = 5.52Hz, 1 H) E384 (7R,8aR)-3-((3,5- Difluoro-4-((2- (trifluoromethyl)pyridin-4- yl)oxy)benzyl) oxy)-7- hydroxy-7,8,8a,9- tetrahydropyrrolo[1′,2′:3,4] imidazo[1,2-

m/z 497.0 (M + H)⁺, 0.86 min (ret. time) CD₃OD: δ ppm 1.73 (d, J = 13.30Hz, 1 H) 2.33- 2.47 (m, 1 H) 3.33-3.40 (m, 1 H) 3.43-3.53 (m, 1 H) 3.93-4.03 (m, 1 H) 4.23-4.36 (m, 2 H) 4.49 (br. s., 1 c]pyrimidin- H) 5.39(d, 1(6H)-one J = 6.02 Hz, 2 H) 5.46 (s, 1 H) 7.16 (d, J = 5.02 Hz, 1 H)7.32 (d, J = 8.78 Hz, 2 H) 7.42 (s, 1 H) 8.61 (d, J = 5.52 Hz, 1 H) E385(7S,8aS)- 3-((3,5-Difluoro-4- ((6-methylpyridin- 3-yl)oxy)benzyl)oxy)-7- hydroxy-7,8,8a,9- tetrahydro pyrrolo[1′,2′:3,4] imidazo[1,2-c]pyrimidin-

m/z 443.1 (M + H)⁺, 0.61 min (ret. time) CDCl₃: δ ppm 1.78-1.85 (m, 1 H)2.38-2.48 (m, 1 H) 2.53 (s, 3 H) 3.43 (s, 2 H) 4.04-4.12 (m, 1 H) 4.30(s, 3 H) 4.60-4.69 (m, 1 H) 5.22 (s, 1 H) 5.38 (s, 2 1(6H)-one H) 7.08(d, J = 8.53 Hz, 3 H) 7.12 (d, J = 3.01 Hz, 1 H) 8.29 (d, J = 2.76 Hz, 1H)

E3865-((((7S,8aR)-7-Amino-1-oxo-1,6,7,8,8a,9-hexahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-3-yl)oxy)methyl)-2-fluorobenzonitrile

To a suspension of tert-butyl((7S,8aR)-3-chloro-1-oxo-1,6,7,8,8a,9-hexahydropyrrolo[1′,2′:3,4]imidazo[1,2-c]pyrimidin-7-yl)carbamate(52.1 mg, 0.159 mmol) and 2-fluoro-5-(hydroxymethyl)benzonitrile (24.10mg, 0.159 mmol) in tetrahydrofuran (THF) (1139 μl) was added NaH (15.94mg, 0.399 mmol) and the reaction was stirred at room temperature for 30min. The mixture was diluted with 5 mL saturated NH₄Cl and extractedwith EtOAc (10 mL×3). The combined organic layer was dried over Na₂SO₄,filtered and concentrated. The crude was purified by HPLC (12 gCombiFlash column, 0-5% MeOH: DCM) to give Boc-protected intermediate asa white solid (LC/MS: m/z 442.0 (M+H)⁺, 0.86 min (ret. time)). To thisintermediate (51.4 mg, 0.116 mmol) in DCM (554 μl) was addedtrifluoroacetic acid (TFA) (277 μl). After 30 min at RT, the mixture wasconcentrated and the crude was purified by reverse-phase HPLC (0-60%CH₃CN:H₂O, 0.1% TFA as modifier) to give the title compound as a whitesolid.

LC/MS: m/z 342.0 (M+H)⁺, 0.51 min (ret. time).

¹H NMR (400 MHz, CDCl₃): δ ppm 1.63-1.72 (m, 1H) 1.95 (dd, J=12.80, 5.77Hz, 1H) 3.10 (d, J=11.29 Hz, 1H) 3.54 (dd, J=11.29, 6.02 Hz, 1H) 3.89(br. s., 1H) 4.02 (dd, J=12.05, 4.02 Hz, 1H) 4.22 (dd, J=11.80, 9.03 Hz,1H) 4.48 (tt, J=9.54, 4.77 Hz, 1H) 5.11 (s, 1H) 5.31 (s, 1H) 5.35 (d,J=13.30 Hz, 1H) 5.44 (d, J=13.30, 1H) 7.20 (t, J=8.53 Hz, 1H) 7.60-7.66(m, 1H) 7.68 (d, J=6.02 Hz, 1H)

The following compounds E387-E392 listed in Table 8 were prepared by aprocedure similar to that described for E386 starting from the requisiteaminoalcohol and benzyl alcohol:

TABLE 8 ¹H NMR Ex # Name Structure LCMS (400 MHz) E387 (7R,8aR)-7-Amino-3-((3,5- difluoro-4- ((2-(trifluoromethyl) pyridin-4-yl)oxy)benzyl) oxy)-7,8,8a,9- tetrahydro- pyrrolo[1′,2′:3,4]imidazo[1,2-

m/z 496.0 (M + H)⁺, 0.75 min (ret. time) CD₃OD: δ ppm 1.47 (dt, J =12.05, 9.66 Hz, 1 H) 2.35 (dt, J = 11.98, 5.93 Hz, 1 H) 3.02 (dd, J =10.67, 6.90 Hz, 1 H) 3.64 (dd, J = 10.54, 7.53 Hz, 1 H) c]pyrimidin-3.70-3.80 (m, 1 H) 1(6H)-one 3.94-4.03 (m, 1 H) 4.14-4.23 (m, 1 H)4.23-4.32 (m, 1H) 5.38 (s, 2 H) 5.41 (s, 1 H) 7.16 (dd, J = 5.65, 2.38Hz, 1 H) 7.28- 7.36 (m, 2 H) 7.43 (d, J = 2.51 Hz, 1 H) 8.61 (d, J =5.77 Hz, 1 H) E388 (7S,8aR)-7- Amino-3- ((3,5-difluoro-4-((2-(trifluoro- methyl)pyridin-4- yl)oxy)benzyl) oxy)-7,8,8a,9-tetrahydropyrrolo [1′,2′:3,4] imidazo[1,2-

m/z 496.1 (M + H)⁺, 0.76 min (ret. time) CDCl₃: δ ppm 1.27 (br. s., 1 H)1.96 (dd, J = 12.05, 5.27 Hz, 1 H) 3.12 (d, J = 11.04 Hz, 1 H) 3.55 (dd,J = 11.17, 5.90 Hz, 1 H) 3.90 (br. s., 1 c]pyrimidin- H) 4.03 (dd,1(6H)-one J = 11.92, 3.64 Hz, 1 H) 4.19- 4.28 (m, 1 H) 4.48 (d, J = 4.27Hz, 1 H) 5.15 (s, 1 H) 5.38 (d, J = 13.80 Hz, 1 H) 5.46 (d, J = 13.30Hz, 1 H) 6.99 (d, J = 3.76 Hz, 1 H) 7.13 (d, J = 8.53 Hz, 2 H) 8.61 (d,J = 5.52 Hz, 1 H) E389 5-((((7R,8aR)- 7-Amino-1- oxo-1,6,7,8,8a,9-hexahydropyrrolo [1′,2′:3,4] imidazo[1,2- c]pyrimidin-3-yl)oxy)methyl)-2- fluorobenzonitrile

m/z 342.1 (M + H)⁺, 0.50 min (ret. time) CDCl₃: δ ppm 1.40-1.50 (m, 1 H)2.37 (dt, J = 12.17, 5.96 Hz, 1 H) 3.00 (dd, J = 10.79, 5.52 Hz, 1 H)3.55 (dd, J = 11.04, 6.53 Hz, 1 H) 3.85 (quin, J = 6.27 Hz, 1 H)4.01-4.09 (m, 1 H) 4.17- 4.29 (m, 2 H) 5.12 (s, 1 H) 5.34-5.46 (m, 2 H)7.20 (t, J = 8.53 Hz, 1 H) 7.64 (d, J = 5.27 Hz, 1 H) 7.67-7.72 (m, 1 H)E390 (7S,8aS)-7- Amino-3- ((3,5-difluoro-4- ((2-(trifluoromethyl)pyridin-4- yl)oxy)benzyl) oxy)-7,8,8a,9- tetrahydropyrrolo [1′,2′:3,4]imidazo[1,2-

m/z 496.0 (M + H)⁺, 0.76 min (ret. time) CDCl₃ δ ppm 1.41-1.51 (m, 1 H)2.32- 2.45 (m, 1 H) 2.97-3.06 (m, 1 H) 3.56 (dd, J = 10.79, 6.53 Hz, 1H) 3.86 (d, J = 5.77 Hz, 1H) 4.06 (d, c]pyrimidin- J = 7.28 Hz, 11(6H)-one H) 4.25 (d, J = 10.54 Hz, 2 H) 5.17 (s, 1 H) 5.43 (s, 2 H)6.99 (d, J = 3.51 Hz, 1 H) 7.14 (d, J = 8.28 Hz, 2 H) 8.61 (d, J = 5.77Hz, 1 H) E391 5-((((7S,8aS)- 7-Amino-1- oxo-1,6,7,8,8a,9-hexahydropyrrolo [1′,2′:3,4] imidazo[1,2- c]pyrimidin- 3-yl)oxy)methyl)-2-fluoro- benzonitrile

m/z 342.0 (M + H)⁺, 0.54 min (ret. time) CDCl₃: δ ppm 1.45 (dt, J =12.42, 7.84 Hz, 1 H) 2.37 (dt, J = 12.23, 6.05 Hz, 1 H) 3.00 (dd, J =11.04, 5.52 Hz, 1 H) 3.55 (dd, J = 10.92, 6.65 Hz, 1 H) 3.85 (t, J =6.53 Hz, 1 H) 4.01-4.09 (m, 1 H) 4.16- 4.30 (m, 2 H) 5.13 (s, 1 H)5.33-5.47 (m, 2 H) 7.21 (t, J = 8.66 Hz, 1 H) 7.61- 7.67 (m, 1 H)7.67-7.71 (m, 1 H) E392 (7R,8aS)-7- Amino-3- ((3,5-difluoro-4-((2-(trifluoromethyl) pyridin-4- yl)oxy)benzyl)oxy)-7,8,8a,9-tetrahydro- pyrrolo[1′,2′:3,4 ]imidazo[1,2- c]pyrimidin-1(6H)-one

m/z 496.2 (M + H)⁺, 0.79 min (ret. time) DMSO-d6: δ ppm 1.52- 1.67 (m, 1H) 1.88 (br. s., 1 H) 3.18 (m, 2 H) 3.53 (dd, J = 11.42, 6.40 Hz, 1 H)3.75- 3.87 (m, 1 H) 3.99- 4.10 (m, 2 H) 4.31 (br. s., 1 H) 4.69 (br. s.,1 H) 5.34 (m, 3 H) 7.32 (br. s., 1 H) 7.46 (d, J = 8.78 Hz, 2 H) 7.68(br. s., 1 H) 8.69 (d, J = 5.52 Hz, 1 H)

E3937-((3,5-Difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-1H-spiro[imidazo[1,2-c]pyrimidine-2,3′-oxetan]-5(3H)-one

NaH (60% wt, 40 mg, 1.00 mmol, 3.7 equiv) was added as solids in oneportion to a chilled solution of(3,5-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)methanol (96 mg,0.40 mmol, 1.5 equiv) in 3 mL of 2-MeTHF. The resulting mixture wasstirred in the ice bath for 5 min, followed by addition of tert-butyl7-chloro-5-oxo-3,5-dihydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,3′-oxetane]-1-carboxylate(84 mg, 0.27 mmol, 1 equiv) as solids in one portion. The mixture wasstirred in the ice bath for 15 min, and followed by removal of thecooling bath. The mixture was stirred at ambient temperature for a totalof 3 h. The mixture was rechilled in the ice bath, and followed byaddition of 0.5 mL of saturated NH₄Cl. The resulting mixture was dilutedwith 1 mL of water, and followed by phase separation. The aqueous wasextracted with 10% MeOH in DCM (2×4 mL). The combined organic was driedover Na₂SO₄, filtered, and evaporated under a stream of nitrogen at 50°C. as a yellowish oily residue. This residue was redissolved in 10% MeOHin DCM and adsorbed onto Isolute. Purification was performed on aTeledyne-Isco Combiflash Rf purification system using a GOLD Redi-Sep 24g silica gel cartridge with gradient elution of 0% A in DCM to 100% A inDCM over a 60 min period (A was a mixture of 80/800/3200 NH₄OH/MeOH/DCM,flow rate at 35 mL/min, UV at 254 nm). The desired product eluted at 17min. Appropriate fractions were combined and concentrated to give thetitle compound (34 mg) as white solids.

LC/MS: m/z 418.1 (M+H)⁺, 0.61 min (ret. time).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.72 (s, 3H) 4.27 (s, 2H) 4.66 (d,J=7.03 Hz, 2H) 4.71 (d, J=7.28 Hz, 2H) 5.09 (s, 1H) 5.24 (s, 2H)7.22-7.32 (m, 3H) 7.59 (s, 1H).

The following compounds in Table 9 were prepared from the requisitebenzyl alcohols and intermediate (e.g., tert-butyl7-chloro-5-oxo-3,5-dihydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,3′-oxetane]-1-carboxylate)via a reaction sequence analogous to that described in Scheme 10:

TABLE 9 Ex # Name Structure LCMS ¹HNMR (400 MHz) E394 7-((3,5-Difluoro-4-((6-methylpyridin- 3-yl)oxy)benzyl) oxy)-1H-spiro [imidazo[1,2-c]pyrimidine- 2,3′-oxetan]- 5(3H)-one

m/z 429.2 (M + H)⁺, 0.54 min (ret. time). DMSO-d6: δ ppm 2.43 (s, 3 H)4.28 (s, 2 H) 4.67 (d, J = 7.28 Hz, 2 H) 4.71 (d, J = 7.28 Hz, 2 H) 5.11(s, 1 H) 5.28 (s, 2 H) 7.21- 7.31 (m, 2 H) 7.35 (d, J = 9.03 Hz, 2 H)8.25 (d, J = 2.76 Hz, 1 H) 9.18 (br. s., 1 H). E395 7-((3,5-difluoro-4-((2- (trifluoromethyl) pyridin-4- yl)oxy)benzyl)oxy)- 1H-spiro[imidazo[1,2-c]pyrimidine- 2,3′-oxetan]- 5(3H)-one

m/z 482.9 (M + H)⁺, 1.96 min (ret. time). E396 7-((3,4- difluorobenzyl)oxy)-1H- spiro[imidazo [1,2-c] pyrimidine- 2,3′-oxetan]- 5(3H)-one

m/z 322.0 (M + H)⁺, 0.57 min (ret. time). DMSO-d₆: δ ppm 4.26 (s, 2 H)4.61- 4.74 (m, 4 H) 5.05 (s, 1 H) 5.22 (s, 2 H) 7.24 (br. s., 1 H)7.37-7.50 (m, 2 H) 9.13 (br. s., 1 H).

E3977-((3,5-Difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)benzyl)oxy)-1-methyl-1H-spiro[imidazo[1,2-c]pyrimidine-2,3′-oxetan]-5(3H)-one

(3,5-Difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)phenyl)methanol (98 mg,0.41 mmol, 1.5 equiv) was dissolved in 1.5 mL of 2-MeTHF in a 20 mLvial, followed by cooling in an ice bath. To this was added NaH (60% wt,38 mg, 0.95 mmol, 3.5 equiv) in one portion. The mixture was stirred inthe ice bath for 5 min, followed by addition of7-chloro-1-methyl-1H-spiro[imidazo[1,2-c]pyrimidine-2,3′-oxetan]-5(3H)-one(62 mg, 0.27 mmol, 1 equiv) in one portion as solids. The mixture wasstirred in the ice bath for 30 min, followed by removing the ice bath.The mixture was stirred at ambient temperature for another 1 h. Themixture was rechilled in the ice bath, followed by addition of 0.5 mL ofsaturated NH₄Cl. The mixture was diluted with 2 mL of water and phaseseparated. The aqueous was extracted with 10% MeOH in DCM (2×4 mL). Thecombined organic was dried over Na₂SO₄, filtered and evaporated under astream of nitrogen at 50° C. to give a pale yellowish residue. Thisresidue was redissolved in 10% MeOH in DCM and adsorbed onto Isolute.Purification was performed on a Teledyne-Isco Combiflash Rf purificationsystem using a GOLD Redi-Sep 24 g silica gel cartridge with gradientelution of 0% A in DCM to 100% A in DCM over a 60 min period (A was amixture of 80/800/3200 NH₄OH/MeOH/DCM, flow rate at 35 mL/min, UV at 254nm). The desired product eluted at 15 min. Appropriate fractions werecombined and concentrated to give the title compound (49 mg) as a whitepowdery solid.

LC/MS: m/z 432.1 (M+H)⁺, 0.68 min (ret. time).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.11 (s, 3H) 3.72 (s, 3H) 4.27 (s, 2H)4.66 (d, J=8.03 Hz, 2H) 4.91 (d, J=7.78 Hz, 2H) 5.26 (s, 2H) 5.29 (s,1H) 7.22-7.30 (m, 3H) 7.59 (s, 1H).

The following compounds in table 10 were prepared from the requisitebenzyl alcohols and intermediate (e.g.,7-chloro-1-methyl-1H-spiro[imidazo[1,2-c]pyrimidine-2,3′-oxetan]-5(3H)-one)via a reaction sequence analogous to that described in Scheme 12:

TABLE 10 Ex # Name Structure LCMS ¹HNMR (400 MHz) E3987-((3,4-Difluorobenzyl) oxy)-1-methyl- 1H-spiro[imidazo[1,2-c]pyrimidine- 2,3′-oxetan]- 5(3H)-one

m/z 336.0 (M + H)⁺, 0.64 min (ret. time). DMSO-d₆: δ ppm 3.10 (s, 3 H)4.27 (s, 2 H) 4.66 (d, J = 7.78 Hz, 2 H) 4.91 (d, J = 7.78 Hz, 2 H) 5.24(s, 2 H) 5.27 (s, 1 H) 7.24 (ddd, J = 6.15, 3.76, 2.38 Hz, 1 H)7.39-7.51 (m, 2 H). E399 3-Fluoro-5-(((1- methyl-5-oxo- 3,5-dihydro-1H-spiro[imidazo[1,2- c]pyrimidine- 2,3′-oxetan]-7- yl)oxy)methyl)-2-((6-methylpyridin- 3-yl)oxy)benzonitrile

m/z 450.2 (M + H)⁺, 2.93 min (ret. time). E400 7-((3,5-Difluoro-4-((6-methyl- pyridin-3- yl)oxy)benzyl) oxy)-1-methyl-1H- spiro[imidazo[1,2-c]pyrimidine- 2,3′-oxetan]- 5(3H)-one

m/z 443.0 (M + H)⁺, 3.21 min (ret. time).

E4017-((3,5-Difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-2′,3′,5′,6′-tetrahydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-pyran]-5(3H)-one

To a 5 mL microwave vial was added(3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol(25.9 mg, 0.085 mmol in THF (2 mL) and this was cooled in ice andstirred for 15 min. To this was added sodium hydride (4.07 mg, 0.170mmol) and solution was stirred in ice for 15 min and tert-butyl7-chloro-5-oxo-2′,3,3′,5,5′,6′-hexahydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-pyran]-1-carboxylate(29 mg, 0.085 mmol) was added at 0° C. and then allowed to warm slowlyto RT overnight. The reaction vessel was sealed and irradiated in aBiotage Initiator microwave using normal power setting to 150° C. for 1hour then allowed to stir at RT over 2 days. LCMS shows reactioncomplete with removal of boc group. The solution was diluted with ethylacetate and water and the layers were separated, and the aqueous layerwas extracted with EtOAc (3×10 mL). The combined organic layers werewashed with saturated NaCl (1×10 mL), dried (MgSO₄), and concentratedunder reduced pressure. The crude product was dissolved in DMSO (1 mL),filtered through a 0.45 m acrodisc, and purified on a Gilson HPLC (YMCC18 S-5 m/12 nm 50×20 mm preparatory column), eluting at 20 mL/min witha linear gradient running from 10% CH₃CN/H₂O (0.1% TFA) to 90% CH₃CN/H₂O(0.1% TFA) over 10 min to yield7-((3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-2′,3′,5′,6′-tetrahydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-pyran]-5(3H)-one(7.4 mg, 0.014 mmol, 6.07% yield as a white powder.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.76 (br. s., 2H) 1.90 (br. s., 2H) 2.60(s, 1H) 3.51 (d, J=8.03 Hz, 2H) 3.75-3.84 (m, 2H) 3.88 (s, 2H) 5.17 (s,2H) 5.90 (s, 1H) 7.03 (d, J=7.78 Hz, 2H) 7.39 (br. s., 1H) 8.39 (s, 1H)8.51 (s, 1H);

LCMS: (MH+)=511 RT=0.86 min.

E4027-((3,4-Difluorobenzyl)oxy)-2′,3′,5′,6′-tetrahydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-pyran]-5(3H)-one

To a 25 mL round bottomed flask was added (3,4-difluorophenyl)methanol(100 □mL, 0.878 mmol) in THF (4 mL) and this was cooled in ice andstirred for 15 min. To this was added 60% sodium hydride (117 mg, 2.93mmol) and solution was stirred in ice for 15 min. Solid tert-butyl7-chloro-5-oxo-2′,3,3′,5,5′,6′-hexahydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-pyran]-1-carboxylate(200 mg, 0.586 mmol) was added then stirred for 30 min in ice. Themixture was treated with water and then ethyl acetate and the organicswere washed with brine and then evaporated to a white powder. The powderwas triturated with hexanes to yield a white powder (92.3 mg, 45%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.59-1.84 (m, 4H) 3.53 (t, J=8.66 Hz,2H) 3.67-3.78 (m, 2H) 3.81 (s, 2H) 4.96-5.07 (m, 1H) 5.23 (s, 2H) 7.26(br. s., 1H) 7.37-7.57 (m, 2H) 8.54 (s, 1H); LCMS: (MH+)=350 rt=0.58min.

E4037-((3,5-Difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-2′,3′,5′,6′-tetrahydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-pyran]-5(3H)-one

To a 5 mL microwave vial was added(3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)phenyl)methanol (73.5 mg,0.293 mmol in tetrahydrofuran (THF) (1 mL) and this was cooled in iceand stirred for 15 min. To this was added 60% sodium hydride (23.40 mg,0.585 mmol) and solution was stirred in ice for 15 min. To a separate 5mL microwave vial was added tert-butyl7-chloro-5-oxo-2′,3,3′,5,5′,6′-hexahydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-pyran]-1-carboxylate(100 mg, 0.293 mmol) in tetrahydrofuran (THF) (1 mL) and solution wascooled in ice and stirred 30 min. The alkoxide solution was addeddropwise via glass pipette and solution was then stirred for 30 min inice and allowed to warm to RT and stirred 30 min. The reaction vesselwas sealed and irradiated in a Biotage Initiator microwave using normalpower setting to 100° C. for 10 min The solution was diluted with ethylacetate and water and the layers were separated, and the aqueous layerwas extracted with EtOAc (3×10 mL). The combined organic layers werewashed with saturated NaCl (1×10 mL), dried (MgSO₄), and concentratedunder reduced pressure. The crude product was dissolved in methanol (1.2mL), filtered through a 0.45 m acrodisc, and purified on a Gilson HPLC(Sunfire 5 m C18 OBD 19×100 mm preparatory column), eluting at 20 mL/minwith a linear gradient running from 5% CH₃CN/H₂O (0.1% TFA) to 50%CH₃CN/H₂O (0.1% TFA) over 12 min. The desired fractions wereconcentrated to an oil which was lyophilized to a white powder:7-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-2′,3′,5′,6′-tetrahydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-pyran]-5(3H)-one(13.2 mg, 0.029 mmol, 9.88% yield).

¹H NMR (400 MHz, CD₃OD) δ ppm 1.85-2.04 (m, 4H) 2.63 (s, 3H) 3.62-3.74(m, 2H) 3.83-3.92 (m, 2H) 4.12 (s, 2H) 5.42 (s, 2H) 5.56-5.64 (m, 1H)7.37 (d, J=8.53 Hz, 2H) 7.55 (d, J=8.53 Hz, 1H) 7.68 (dd, J=8.78, 3.01Hz, 1H) 8.36 (d, J=2.76 Hz, 1H); LCMS: (MH+)=457 RT=0.58 min.

E4042-Fluoro-5-(2-((5-oxo-2′,3,3′,5,5′,6′-hexahydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-pyran]-7-yl)oxy)ethyl)benzonitrile

To a 20 mL scintillation vial was added2-fluoro-5-(2-hydroxyethyl)benzonitrile (72.5 mg, 0.439 mmol) intetrahydrofuran (THF) (2 mL) and this was cooled in ice and stirred for15 min. To this was added 60% NaH (58.5 mg, 1.463 mmol) and solution wasstirred in ice for 15 min. Solid tert-butyl7-chloro-5-oxo-2′,3,3′,5,5′,6′-hexahydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-pyran]-1-carboxylate(100 mg, 0.293 mmol) was added then stirred for 1 h in ice, solution wasallowed to warm to RT and stirred 1 h. The mixture was treated withwater and then ethyl acetate and the organics were washed with brine andthen evaporated to an oil. The crude product was dissolved in DMSO (1.2mL), filtered through a 0.45 mm acrodisc, and purified on a Gilson HPLC(Sunfire 5 mm C18 OBD 19×100 mm preparatory column), eluting at 20mL/min with a linear gradient running from 10% CH₃CN/H₂O (0.1% TFA) to50% CH₃CN/H₂O (0.1% TFA) over 12 min. The desired fractions wereconcentrated by rotovap to an oil which was lyophilized to a whitepowder2-fluoro-5-(2-((5-oxo-2′,3,3′,5,5′,6′-hexahydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-pyran]-7-yl)oxy)ethyl)benzonitrile(35 mg, 0.094 mmol, 32.0% yield).

¹H NMR (400 MHz, CDCl₃) δ ppm 1.92-2.09 (m, 4H) 3.12 (t, J=6.27 Hz, 2H)3.66 (br. s., 2H) 3.93-4.05 (m, 4H) 4.52 (t, J=6.27 Hz, 2H) 6.04 (s, 1H)7.20 (s, 1H) 7.55 (d, J=6.53 Hz, 2H); LCMS: (MH+)=341 rt=0.56 min.

E4057-((3,5-Difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-1-methyl-2′,3′,5′,6′-tetrahydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-pyran]-5(3H)-one

To a 5 mL microwave vial was added(3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)phenyl)methanol (73.7 mg,0.293 mmol) in THF (1 mL) and this was cooled in ice and stirred for 15min. To this was added 60% sodium hydride (23.46 mg, 0.587 mmol) andsolution was stirred in ice for 15 min. To a separate 5 mL microwavevial was added7-chloro-1-methyl-2′,3′,5′,6′-tetrahydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-pyran]-5(3H)-one(75 mg, 0.293 mmol) in tetrahydrofuran (THF) (1.000 mL) and solution wascooled in ice and stirred 30 min. The alkoxide solution was addeddropwise via glass pipette and solution was then stirred for 30 min inice; reaction complete by Icms. The solution was diluted with ethylacetate and water and the layers were separated, and the aqueous layerwas extracted with EtOAc (3×10 mL). The combined organic layers werewashed with saturated NaCl (1×10 mL), dried (MgSO₄), and concentratedunder reduced pressure. The crude product was dissolved in methanol (1.2mL), filtered through a 0.45 μm acrodisc, and purified on a Gilson HPLC(Sunfire 5 m C18 OBD 19×100 mm preparatory column), eluting at 20 mL/minwith a linear gradient running from 5% CH₃CN/H₂O (0.1% TFA) to 50%CH₃CN/H₂O (0.1% TFA) over 12 min. The desired fractions were not pure.The residue was dissolved in THF (1.000 mL) and treated with 60% sodiumhydride (23.46 mg, 0.587 mmol) and stirred for 30 min at RT. To this wasadded Boc-anhydride (0.068 mL, 0.293 mmol) and solution was stirred for30 min. The Boc group was added to the impurity (alcohol) which enabledseparation of desired compound. Solution was diluted with 2 mL ofmethanol and evaporated, and residue was dissolved in 1 mL of DMF,filtered through an acrodisk (0.45) and was purified on a Gilson HPLC(Sunfire 5 m C18 OBD 19×100 mm preparatory column), eluting at 20 mL/minwith a linear gradient running from 10% CH₃CN/H₂O (0.1% TFA) to 90%CH₃CN/H₂O (0.1% TFA) over 12 min. The fraction was evaporated andlyophilized to yield7-((3,5-difluoro-4-((6-methylpyridin-3-yl)oxy)benzyl)oxy)-1-methyl-2′,3′,5′,6′-tetrahydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-pyran]-5(3H)-one(8 mg, 0.017 mmol, 5.68% yield) as a white powder.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.74 (d, J=13.05 Hz, 2H) 2.22 (td,J=12.80, 5.27 Hz, 2H) 2.71 (s, 3H) 3.17 (s, 3H) 3.55 (t, J=12.30 Hz, 2H)4.07 (dd, J=12.05, 4.77 Hz, 2H) 4.23 (s, 2H) 5.46 (s, 2H) 5.91 (s, 1H)7.41 (d, J=8.53 Hz, 2H) 7.74 (d, J=8.78 Hz, 1H) 7.93 (dd, J=8.78, 2.76Hz, 1H) 8.54 (d, J=3.01 Hz, 1H);

LCMS: (MH+)=471, RT=0.66 min.

E4067-((3,4-Difluorobenzyl)oxy)-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidin]-5(3H)-one

To a 25 mL round bottomed flask was added tert-butyl7-((3,4-difluorobenzyl)oxy)-5-oxo-3,5-dihydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidine]-1′-carboxylate(93 mg, 0.207 mmol) and 4M HCl in dioxane (2 mL, 8 mmol) then stirredfor 1 h at RT. The solution was evaporated to yield7-((3,4-difluorobenzyl)oxy)-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidin]-5(3H)-one(56 mg, 0.154 mmol, 74.4% yield) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ ppm 2.07-2.31 (m, 4H) 3.40-3.51 (m, 2H)3.64-3.81 (m, 1H) 4.09-4.24 (m, 2H) 5.37 (s, 2H) 5.65 (s, 1H) 7.27-7.40(m, 2H) 7.41-7.52 (m, 1H); LCMS: (MH+)=349 rt=0.51 min.

E407 and E4081′-Acetyl-7-((3,4-difluorobenzyl)oxy)-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidin]-5(3H)-one(E407)

and1,1′-(7-((3,4-difluorobenzyl)oxy)-5-oxo-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidin]-1,1′(3H,5H)-diyl)diethanone(E408)

To a 2 mL microwave vial was added tert-butyl7-((3,4-difluorobenzyl)oxy)-5-oxo-3,5-dihydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidine]-1′-carboxylate(25 mg, 0.063 mmol) in DCM (2 mL). To this was added DIEA (72 L, 0.431mmol) and then acetyl chloride (16 L, 0.215 mmol) at RT. Upon additionof acetyl chloride solution turned from cloudy to clear with a slightwarming observed. Stirring for 10 min and check by Icms shows 2:1 ratioof diacetylated to monoacetylated products. The solution was evaporatedand purified by Gilson (sunfire-c18-small-gradient: 10%Acetonitrile/water to 60% over 10 min. The residues were individuallylyophilized to yield:

1′-acetyl-7-((3,4-difluorobenzyl)oxy)-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidin]-5(3H)-one(10 mg, 34%) as a white powder.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.76-2.08 (m, 4H) 2.16 (s, 3H) 3.50-3.66(m, 2H) 3.74 (dd, J=13.55, 6.78 Hz, 1H) 3.87 (dd, J=14.68, 6.15 Hz, 1H)5.36 (s, 2H) 7.26-7.52 (m, 3H); LCMS: (MH+)=391 rt=0.61 min, and

1,1′-(7-((3,4-difluorobenzyl)oxy)-5-oxo-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidin]-1,1′(3H,5H)-diyl)diethanone(14 mg, 41%) as a white powder.

¹H NMR (400 MHz, CD₃OD) δ ppm 1.82 (dd, J=17.07, 12.30 Hz, 2H) 2.16 (s,3H) 2.37-2.52 (m, 3H) 2.65-2.77 (m, 2H) 2.79-2.87 (m, 1H) 3.20-3.30 (m,1H) 4.02 (d, J=14.30 Hz, 1H) 4.16 (s, 2H) 4.63 (d, J=8.78 Hz, 1H)5.34-5.42 (m, 2H) 5.99 (s, 1H) 7.21-7.32 (m, 2H) 7.36-7.49 (m, 1H);LCMS: (MH+)=433 rt=0.81 min.

E4091′-(Cyclopropanecarbonyl)-7-((3,4-difluorobenzyl)oxy)-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidin]-5(3H)-one

To a 2 mL microwave vial was added7-((3,4-difluorobenzyl)oxy)-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidin]-5(3H)-one(20 mg, 0.057 mmol) in DCM (2 mL). To this was added DIEA (72 L, 0.431mmol) and then portionwise addition of cyclopropanecarbonyl chloride(5.78 μl, 0.063 mmol) [60 ml dissolved in 1 mL DCM-add 100 mL (4×25 mLbatches)] at 0° C. Upon addition of acid chloride solution turned fromcloudy to clear; after 30 min solution was evaporated under a stream ofnitrogen. The crude product was dissolved in DMSO (1 mL), filteredthrough a 0.45 mm acrodisc, and purified on a Gilson HPLC (YMC C18 S-5mm/12 nm 50×20 mm preparatory column), eluting at 20 mL/min with alinear gradient running from 10% CH₃CN/H₂O (0.1% TFA) to 90% CH₃CN/H₂O(0.1% TFA) over 10 min. The desired fractions were concentrated under astream of nitrogen at 50° C., giving an oil which was lyophilized to awhite powder1′-(cyclopropanecarbonyl)-7-((3,4-difluorobenzyl)oxy)-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidin]-5(3H)-one(9.3 mg, 0.022 mmol, 38.5% yield).

¹H NMR (400 MHz, CD₃OD) δ ppm 0.75-0.98 (m, 4H) 1.79-2.08 (m, 4H) 3.56(br. s., 1H) 3.75-4.02 (m, 4H) 4.08 (s, 2H) 5.29-5.39 (m, 2H) 5.46 (s,1H) 7.33 (d, J=9.54 Hz, 1H) 7.39-7.49 (m, 1H); LCMS: (MH+)=417 rt=0.67min.

E4101′-(Cyclopropylsulfonyl)-7-((3,4-difluorobenzyl)oxy)-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidin]-5(3H)-one

To a 2 mL microwave vial was added tert-butyl7-((3,4-difluorobenzyl)oxy)-5-oxo-3,5-dihydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidine]-1′-carboxylate(36 mg, 0.080 mmol) and 4 M HCl (0.803 mL, 3.21 mmol) and solution wasstirred overnight, then solution was evaporated. The residue wasdissolved in DCM (2 mL) and DIEA (0.084 mL, 0.482 mmol) was addedfollowed by portionwise addition of cyclopropanesulfonyl chloride (9.81μl, 0.096 mmol) [98 ml dissolved in 1 mL DCM-add 100 mL (4×25 mLbatches)] at 0° C. Solution was allowed to warm to RT and stirred 1 h.The crude product was dissolved in DMSO (1 mL), filtered through a 0.45mm acrodisc, and purified on a Gilson HPLC (YMC C18 S-5 mm/12 nm 50×20mm preparatory column), eluting at 20 mL/min with a linear gradientrunning from 10% CH₃CN/H₂O (0.1% TFA) to 90% CH₃CN/H₂O (0.1% TFA) over10 min. The desired fractions were concentrated by rotovap giving an oilwhich was lyophilized to a white powder1′-(cyclopropylsulfonyl)-7-((3,4-difluorobenzyl)oxy)-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidin]-5(3H)-one(17.5 mg, 0.037 mmol, 45.8% yield).

¹H NMR (400 MHz, CD₃OD) δ ppm 1.00-1.15 (m, 4H) 1.97-2.12 (m, 4H) 2.53(t, J=5.77 Hz, 1H) 3.37 (d, J=8.78 Hz, 2H) 3.49-3.64 (m, 2H) 4.09 (s,2H) 5.35 (s, 2H) 5.59 (s, 1H) 7.25-7.51 (m, 3H); LCMS: (MH+)=453 rt=0.70min.

E4111′-Benzyl-7-((3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidin]-5(3H)-one

To a 5 mL microwave vial was added(3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol(177 mg, 0.580 mmol) in THF (3 mL) and to this was added 60% sodiumhydride (46.4 mg, 1.160 mmol) and solution was stirred for 15 min andtert-butyl1′-benzyl-7-chloro-5-oxo-3,5-dihydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidine]-1-carboxylate(250 mg, 0.580 mmol) was added at rt and then was stirred 1 h. Thesolution was diluted with ethyl acetate and water and the layers wereseparated, and the aqueous layer was extracted with EtOAc. The combinedorganic layers were washed with saturated NaCl, dried (MgSO₄), andconcentrated under reduced pressure. The crude product was dissolved inmethanol (2 mL), filtered through a 0.45 m acrodisc, and purified on aGilson HPLC (YMC C18 S-5 m/12 nm 50×20 mm preparatory column), elutingat 20 mL/min with a linear gradient running from 30% CH₃CN/H₂O (0.1%TFA) to 90% CH₃CN/H₂O (0.1% TFA) over 10 min. The desired fractions wereconcentrated by rotovap to yield tert-butyl1′-benzyl-7-((3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-5-oxo-3,5-dihydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidine]-1-carboxylate(164 mg, 0.234 mmol, 40.4% yield) as a white solid. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.50 (br. s., 9H) 1.86 (d, J=13.05 Hz, 2H) 2.98-3.31 (m,4H) 3.64 (d, J=10.04 Hz, 2H) 4.22 (s, 2H) 4.40 (s, 2H) 5.22 (s, 2H) 6.31(br. s., 1H) 6.91 (d, J=8.28 Hz, 2H) 7.28-7.50 (m, 6H) 8.45 (br. s., 1H)8.57 (s, 1H); LCMS: (MH+)=700 RT=1.13 min. To a 4 mL screw cap vial wasadded tert-butyl1′-benzyl-7-((3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-5-oxo-3,5-dihydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidine]-1-carboxylate(35 mg, 0.050 mmol) and 4 M HCl in dioxane (1 mL, 4.00 mmol) andsolution was stirred at RT for 4 h. The solution was evaporated under astream of nitrogen and the residue was lyophilized to yield1′-benzyl-7-((3,5-difluoro-4-((5-(trifluoromethyl)pyridin-3-yl)oxy)benzyl)oxy)-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidin]-5(3H)-one(16.2 mg, 0.027 mmol, 54.0% yield) as a white solid. ¹H NMR (400 MHz,CD₃OD) δ ppm 2.22 (br. s., 4H) 3.42-3.53 (m, 4H) 3.62-3.69 (m, 2H) 4.00(s, 1H) 4.18 (s, 1H) 4.33 (d, J=18.82 Hz, 2H) 5.36 (d, J=5.02 Hz, 2H)5.67-5.82 (m, 1H) 7.32 (dd, J=8.16, 4.14 Hz, 2H) 7.42 (br. s., 3H) 7.53(br. s., 2H) 7.80 (d, J=9.03 Hz, 1H) 8.62 (br. s., 1H); LCMS: (MH+)=600RT=0.86 min.

E4125-(((1′-Benzyl-5-oxo-3,5-dihydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidin]-7-yl)oxy)methyl)-2-fluorobenzonitrile

To a 5 mL microwave vial was added2-fluoro-5-(hydroxymethyl)benzonitrile (88 mg, 0.580 mmol) intetrahydrofuran (THF) (3 mL) and to this was added 60% sodium hydride(46.4 mg, 1.160 mmol) and solution was stirred for 15 min and then addedto reaction vessel and stirred at RT for 1 h. The solution was dilutedwith ethyl acetate and water and the layers were separated, and theaqueous layer was extracted with EtOAc. The combined organic layers werewashed with saturated NaCl, dried over MgSO₄ and concentrated underreduced pressure. The crude product was dissolved in methanol (2 mL),filtered through a 0.45 m acrodisc, and purified on a Gilson HPLC (YMCC18 S-5 m/12 nm 50×20 mm preparatory column), eluting at 20 mL/min witha linear gradient running from 10% CH₃CN/H₂O (0.1% TFA) to 90% CH₃CN/H₂O(0.1% TFA) over 10 min. The desired fractions were concentrated byrotovap to yield tert-butyl1′-benzyl-7-((3-cyano-4-fluorobenzyl)oxy)-5-oxo-3,5-dihydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidine]-1-carboxylate(22 mg, 0.040 mmol, 6.95% yield) as an oil. ¹H NMR (400 MHz, CDCl₃) δppm 1.49 (br. s., 9H) 1.84 (d, J=13.30 Hz, 2H) 3.00 (d, J=13.05 Hz, 2H)3.06-3.18 (m, 2H) 3.67 (d, J=11.80 Hz, 2H) 4.13 (s, 2H) 4.31 (br. s.,2H) 5.25 (s, 2H) 6.25 (br. s., 1H) 7.09 (t, J=8.66 Hz, 1H) 7.19 (s, 1H)7.33-7.42 (m, 5H) 7.46 (br. s., 1H) 7.52 (d, J=5.02 Hz, 1H); LCMS:(MH+)=546 RT=0.93 min. To a 4 mL screw cap vial was added tert-butyl1′-benzyl-7-((3-cyano-4-fluorobenzyl)oxy)-5-oxo-3,5-dihydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidine]-1-carboxylate(22 mg, 0.040 mmol) and 4 M HCl in dioxane (1 mL, 4.00 mmol) andsolution was stirred at RT overnight. Solution was evaporated under astream of nitrogen and the residue was lyophilized to yield5-(((1′-benzyl-5-oxo-3,5-dihydro-1H-spiro[imidazo[1,2-c]pyrimidine-2,4′-piperidin]-7-yl)oxy)methyl)-2-fluorobenzonitrile(8.7 mg, 0.020 mmol, 48.4% yield) as a white solid. ¹H NMR (400 MHz,CD₃OD) δ ppm 3.45-3.51 (m, 4H) 3.54-3.59 (t, 2H) 3.62-3.67 (m, 2H) 3.98(br. s., 1H) 4.16 (br. s., 1H) 4.26-4.37 (m, 2H) 5.32 (d, J=5.27 Hz, 2H)5.60-5.82 (m, 1H) 7.34-7.39 (m, 1H) 7.42 (br. s., 3H) 7.50 (br. s., 2H)7.76 (br. s., 1H) 7.83 (br. s., 1H); LCMS: (MH+)=445 RT=0.61 min.

Table 11 provides more exemplary compounds. Example Nos. 413-430 wereprepared according to methods similar to the above described reactions.

TABLE 11 Example No. Compound name Analytical data 4137′-((3-fluorobenzyl)oxy)-1′-methyl-1′H- LCMS: Rt = 3.472 min,spiro[cyclobutane-1,2′-imidazo[1,2- [M + H]+ = 316c]pyrimidin]-5′(3′H)-one 414 1′-methyl-7′-((3,4,5-trifluorobenzyl)oxy)-LCMS: Rt = 4.417 min, 1′H-spiro[cyclopentane-1,2′-imidazo[1,2- [M + H]+= 366 c]pyrimidin]-5′(3′H)-one 4151′-methyl-7′-((2,4,5-trifluorobenzyl)oxy)- LCMS: Rt = 3.359 min,1′H-spiro[cyclopentane-1,2′-imidazo[1,2- [M + H]+ = 366c]pyrimidin]-5′(3′H)-one 416 7′-((2,4-difluorobenzyl)oxy)-1′-methyl-1′H-LCMS: Rt = 3.524 min, spiro[cyclobutane-1,2′-imidazo[1,2- [M + H]+ = 334c]pyrimidin]-5′(3′H)-one 417 7′-((3-fluorobenzyl)oxy)-1′-methyl-1′H-LCMS: Rt = 3.832 min, spiro[cyclohexane-1,2′-imidazo[1,2- [M + H]+ = 344c]pyrimidin]-5′(3′H)-one 418 7′-((3-fluorobenzyl)oxy)-1′-methyl-1′H-LCMS: Rt = 4.150 min, spiro[cyclopentane-1,2′-imidazo[1,2- [M + H]+ =330 c]pyrimidin]-5′(3′H)-one 4197′-((2,4-difluorobenzyl)oxy)-1′-methyl-1′H- LCMS: Rt = 3.105 min,spiro[cyclopentane-1,2′-imidazo[1,2- [M+H]+ = 348c]pyrimidin]-5′(3′H)-one 420 7′-((2,3-difluorobenzyl)oxy)-1′-methyl-1′H-LCMS: Rt = 3.995 min, spiro[cyclobutane-1,2′-imidazo[1,2- [M+H]+ = 334c]pyrimidin]-5′(3′H)-one 421 4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-LCMS: Rt = 3.777 min, spiro[cyclobutane-1,2′-imidazo[1,2- [M + H]+ = 323c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile 4221′-methyl-7′-((3,4,5-trifluorobenzyl)oxy)- LCMS: Rt = 4.063 min,1′H-spiro[cyclohexane-1,2′-imidazo[1,2- [M + H]+ = 380c]pyrimidin]-5′(3′H)-one 423 1′-methyl-7′-((3,4,5-trifluorobenzyl)oxy)-LCMS: Rt = 4.165 min, 1′H-spiro[cyclobutane-1,2′-imidazo[1,2- [M+H]+ =352 c]pyrimidin]-5′(3′H)-one 4244-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H- LCMS: Rt = 3.884 min,spiro[cyclopentane-1,2′-imidazo[1,2- [M + H]+ = 337c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile 4257′-((2,3-difluorobenzyl)oxy)-1′-methyl-1′H- LCMS: Rt = 3.876 min,spiro[cyclohexane-1,2′-imidazo[1,2- [M + H]+ = 362c]pyrimidin]-5′(3′H)-one 426 7′-((2,3-difluorobenzyl)oxy)-1′-methyl-1′H-LCMS: Rt = 3.133 min, spiro[cyclopentane-1,2′-imidazo[1,2- [M+H]+ = 348c]pyrimidin]-5′(3′H)-one 427 7′-((2,4-difluorobenzyl)oxy)-1′-methyl-1′H-LCMS: Rt = 3.871 min, spiro[cyclohexane-1,2′-imidazo[1,2- [M + H]+ = 362c]pyrimidin]-5′(3′H)-one 428 1′-methyl-7′-((2,4,5-trifluorobenzyl)oxy)-LCMS: Rt = 3.982 min, 1′H-spiro[cyclohexane-1,2′-imidazo[1,2- [M + H]+ =380 c]pyrimidin]-5′(3′H)-one 4291′-methyl-7′-((2,4,5-trifluorobenzyl)oxy)- LCMS: Rt = 3.647 min,1′H-spiro[cyclobutane-1,2′-imidazo[1,2- [M + H]+ = 352c]pyrimidin]-5′(3′H)-one 430 4-(((1′-methyl-5′-oxo-3′,5′-dihydro-1′H-LCMS: Rt = 4.042 min, spiro[cyclohexane-1,2′-imidazo[1,2- [M + H]+ = 351c]pyrimidin]-7′-yl)oxy)methyl)benzonitrile

D. Biological Assays and Data

The compounds of present invention are Lp-PLA₂ inhibitors, and may beuseful in the treatment and prevention of diseases mediated by Lp-PLA₂.The biological activities of the compounds of present invention can bedetermined by using any suitable assay for determining the activity of acompound as a Lp-PLA₂ inhibitor, as well as tissue and in vivo models.

The biological activity data for each compound was either reported in atleast one experiment or the average of multiple experiments. It isunderstood that the data described herein may have reasonable variationsdepending on the specific conditions and procedures used by the personconducting the experiments.

Lipoprotein-Associated Phospholipase A2 (Lp-PLA₂) Biochemical Assay

(1) Recombinant Human Lp-PLA₂ Assays (rhLp-PLA₂)

(1a) PED6 Assay

N-((6-(2,4-Dinitrophenyl)amino)-hexanoyl)-2-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)-1-hexadecanoyl-sn-glycero-3-phosphoethanolamine,triethylammonium salt (PED6) is a commercially availablefluorescently-labeled phospholipid, which is commercially available fromInvitrogene and Molecular Probes. There is a quenching para-nitro phenyl(PNP) group in the sn3 position and a Bodipy fluorescein (FL) group inthe sn2 position. Upon cleavage with Lp-PLA₂, the Bodipy FL group isliberated and then may result in an increase in fluorescence. Inhibitorsof Lp-PLA₂ therefore prevent this cleavage and no fluorescent increaseis observed.

The PED6 assay was run as an unquenched 10 μL assay. The source platecontaining the compounds to be tested was prepared by making 1:3 (byvolume) serial dilution of the compounds within DMSO on 384-wellmicroplate. Then, 0.01 μL of the compounds on compound source plate weretransferred into 384 well Greiner 784076 (black) plates using ECHOliquid dispenser. 5 μL of recombinant human Lp-PLA₂ enzyme (4 nM)rhLp-PLA₂ in assay buffer of 50 mM HEPES, pH 7.4, 150 mM NaCl, 1 mMCHAPS) was added to each well of the plate. Plates were centrifuged for10 sec at 500 rpm. After 30 minutes preincubation, 5 μL of substrate (4μM PED6 [from 5 mM DMSO stock] in assay buffer of 50 mM HEPES, pH 7.4,150 mM NaCl, 1 mM CHAPS) was added to 384 well Greiner 784076 (black)plates. Plates were centrifuged for 10 sec at 500 rpm. The plate wascovered to protect it from light and incubated for 20 min at roomtemperature. The plates were read for fluorescence intensity at ex:480/em: 540 using ViewLux microplate imager for Envisionspectrofluroimeters. pIC50 data, curve and QC analysis was conducted byusing XL fit module in Excel.

(1b) hrThioPAF Assay

1-O-Hexadecyl-2-deoxy-2-thio-S-acetyl-sn-glyceryl-3-phosphorylcholine(2-thio-PAF) is a substrate for PAF-hydrolases (PAF-AH) commerciallyavailable from Cayman Chemical. Upon cleavage with PAF-AH, the freethiol is released at the sn-2 position and can then react with7-diethylamino-3-(4′-maleimidylphenyl)-4-methylcoumarin (CPM) athiol-reactive coumarin. This reaction (Michael addition) results in anincrease in fluorescence. Inhibitors of Lp-PLA₂ therefore prevent thiscleavage and no fluorescent increase is observed.

The Thio-PAF assay was run as an unquenched 20 μL assay. The sourceplate containing the compounds to be tested was prepared by making 1:3(by volume) serial dilution of the compounds within DMSO on 384-wellmicroplate. Then, 5 μL of the compounds on compound source plate weretransferred into 384 well Greiner 784076 (black) plates using STAR+(Hamilton) liquid dispenser. 10 μL of recombinant human Lp-PLA₂ enzyme(20 pM rhLp-PLA₂ in assay buffer of 50 mM HEPES, pH 7.4, 150 mM NaCl, 1mM CHAPS) was added to each well of the plate. 5 μL of substratecomprising 40 μM 2-thio-PAF [from ethanol stock], 40 μM CPM [from a DMSOstock] and 400 μM NEM (N-ethylmaleimide) [made fresh daily in DMSO] inassay buffer (50 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM CHAPS) was added to384 well Greiner 784076 black plates. Plates were vortexed for 10 sec.The plate was covered to protect it from light and incubated for 20 minat 25° C. The plates were read for fluorescence intensity at ex: 380nm/em: 485 nm using Envision plate reader (Perkin Elmer). Raw data weretransferred to Excel software and pIC50 data, curve and QC analysis wasconducted by using XL fit module in Excel.

(1c) Alternative PED6 Assay

N-((6-(2,4-Dinitrophenyl)amino)-hexanoyl)-2-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)-1-hexadecanoyl-sn-glycero-3-phosphoethanolamine,triethylammonium salt (PED6) is a commercially availablefluorescently-labeled phospholipid, which is commercially available fromInvitrogene and Molecular Probes. There is a quenching para-nitro phenyl(PNP) group in the sn3 position and a Bodipy fluorescein (FL) group inthe sn2 position. Upon cleavage with Lp-PLA₂, the Bodipy FL group isliberated and then may result in an increase in fluorescence. Inhibitorsof Lp-PLA₂ therefore prevent this cleavage and no fluorescent increaseis observed.

The PED6 assay was run as an unquenched 10 μL assay. The source platecontaining the compounds to be tested was prepared at 10 mM in DMSO on384-well microplate. Then, 0.01 μL of the compounds on compound sourceplate were transferred into 384 well Greiner 784076 (black) plates usingECHO liquid dispenser (the final concentration of compound is 10 uM). 5μL of recombinant human Lp-PLA₂ enzyme (final concentration is 110 pM)rhLp-PLA₂ in assay buffer of 50 mM HEPES, pH 7.4, 150 mM NaCl, 1 mMCHAPS) was added to each well of the plate. Plates were centrifuged for10 sec at 500 rpm. After 30 minutes preincubation, 5 μL of substrate(final concentration is 5 μM) PED6 [from 5 mM DMSO stock] in assaybuffer of 50 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM CHAPS) was added to 384well Greiner 784076 (black) plates. Plates were centrifuged for 10 secat 500 rpm. The plate was covered to protect it from light and incubatedfor 20 min at room temperature. The plates were read for fluorescenceintensity at ex: 480/em: 540 using ViewLux microplate imager forEnvision spectrofluroimeters. This assay was used to qualitativelymeasure whether the tested compound demonstrates inhibition activity.

Examples 1-167 and 413-430 were tested in the (1a) PED6 assay, Examples168-265 were tested in (1c) alternative PED6 assay, and Example 266-412,was tested in (1b) hrThioPAF assay. All tested Examples except Examples318, 355, 376, 378, 379, and 380, 421, 424 and 430 were found todemonstrate inhibition activity to Lp-PLA₂. The pIC₅₀ value forcompounds tested under (1a) and (1b) was either reported in at least oneexperiment or the average of multiple experiments. (1c) alternative PED6assay was used to test whether the compounds have inhibition activity toLp-PLA2, but not the actual pIC₅₀ value.

The pIC₅₀ values in the recombinant human Lp-PLA₂ assay ((1a) and (1b))for Examples 1-167, 266-317, 319-354, 356-375, 377, 381-412, 413-420,422, 423, and 425-429 were at least 5.0.

The pIC₅₀ values in the recombinant human Lp-PLA₂ assay ((1a) and (1b))for Examples 1-3, 5, 6, 8, 10-12, 14-167, 266, 267, 269-271, 273, 274,279-308, 310, 313, 315, 317, 320-325, 327-347, 349-352, 356-361, 364,366-373, 381-388, 390-392 393-403, 405, 407-412, 413-420, 422, 423, and425-429 were at least 7.0.

The pIC₅₀ values in the recombinant human Lp-PLA₂ assay ((1a) and (1b))for Examples 10-12, 17, 19-26, 28, 37-42, 44-49, 67, 71, 75, 77-79, 81,83, 85, 87, 88, 90, 91, 107, 110-113, 115, 118, 119, 124, 125, 134, 135,141, 142, 149, 151, 154, 162, 164, 166, 273, 351, 352, 368, 371, 372,383, 388, 395, 401 and 409-411 were at least 9.0.

For example, the pIC50 values of recombinant human Lp-PLA₂ assay ((1a)and (1b)) for following examples are:

Example No. rhLp-PLA₂ (pIC50) 67 9.8 71 9.5 107 10.4 109 8.9 110 9.3 11310.5 115 9.0 124 9.3 125 10.2 128 8.0 338 8.0 352 9.3 395 9.1 401 9.2

(2) PLA2 VIIB Assay

(2a) PLA2 VIIB Assay

PLA2 VIIB (also known as Novel Serine Dependent Lipase, NSDL) is aserine hydrolase with 40% amino acid identity with human Lp-PLA₂.Sequence comparisons indicate that the PLA VIIB active site catalytictriad positions are similar to those of Lp-PLA₂. Similar to Lp-PLA₂, itis capable of hydrolyzing oxidatively modified phospholipids and may beassayed using known Lp-PLA₂ substrates.

Upon cleavage by a phospholipase, PLA2 VIIB liberates a fluorescentBodipy group. Recombinant human PLA2 VIIB is used as the phospholipasesource in this assay, and compounds are screened to test their degree ofinhibition in this assay. The assay is used to determine the degree ofselectivity of the testing compounds between PLA2 VIIB and Lp-PLA₂.

The PLA2 VIIB assay was applied as an unquenched 10 μL assay. The sourceplate containing the compounds is prepared by making 1:3 (by volume)serial dilution of the compounds with pure DMSO on 384-well microplate.0.01 μL of compounds on the compound source plate were transferred into384 well Greiner 784076 (black) plates by ECHO liquid dispenser. 5 μL ofNovel Serine Dependent Lipase (NSDL) enzyme (5 nM NSDL in assay bufferof 50 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM CHAPS) was added to each well.Alternatively, in some instances, this step was carried out by adding 10μL of recombinant human PLA2 VIIB (200 pM rhPLA₂ VIIB in assay buffer of50 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM CHAPS) to each well. Plates werecentrifuged for 10 sec at 500 rpm. After 30 minutes preincubation, 5 μLof substrate (5 μM PED6 [from 5 mM DMSO stock] in assay buffer of 50 mMHEPES, pH 7.4, 150 mM NaCl, 1 mM CHAPS) was added to 384 well Greiner784076 (black) low-volume plates. Plates were kinetic read by startingread immediately after PED6 addition at ex: 480/em: 540 using ViewLuxmicroplate reader or Envision spectrofluorimeters. IC 50 data (which maybe converted to pIC50 data), curve and QC analysis was conducted usingXLfit module in Excel.

(2b) Alternative PLA2 VIIB Assay

1-O-hexadecyl-2-deoxy-2-thio-S-acetyl-sn-glyceryl-3-phosphorylcholine(2-thio-PAF) is a substrate for PAF-hydrolases (PAF-AH) commerciallyavailable from Cayman Chemical. Upon cleavage with PAF-AH, the freethiol is released at the sn-2 position and can then react with7-diethylamino-3-(4′-maleimidylphenyl)-4-methylcoumarin (CPM) athiol-reactive coumarin. This reaction (Michael addition) results in anincrease in fluorescence. Inhibitors of PLA₂-VIIB therefore prevent thiscleavage and no fluorescent increase is observed.

The Thio-PAF assay was run as an unquenched 20 μL assay. The sourceplate containing the compounds to be tested was prepared by making 1:3(by volume) serial dilution of the compounds within DMSO on 384-wellmicroplate. Then, 5 μL of the compounds on compound source plate weretransferred into 384 well Greiner 784076 (black) plates using STAR+(Hamilton) liquid dispenser. 10 μL of recombinant human PLA₂-VIIB enzyme(200 pM rhPLA2-VIIB in assay buffer of 50 mM HEPES, pH 7.4, 150 mM NaCl,1 mM CHAPS) was added to each well of the plate. 5 μL of substratecomprising 40 μM 2-thio-PAF [from ethanol stock], 40 μM CPM [from a DMSOstock] and 400 μM NEM (N-ethylmaleimide) [made fresh daily in DMSO] inassay buffer (50 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM CHAPS) was added to384 well Greiner 784076 black plates. Plates were vortexed for 10 sec.The plate was covered to protect it from light and incubated for 20 minat 25° C. The plates were read for fluorescence intensity at ex: 380nm/em: 485 nm using Envision plate reader (Perkin Elmer). Raw data weretransferred to Excel software and pIC50 data, curve and QC analysis wasconducted by using XL fit module in Excel.

Examples 1-9, 11-105, 107-193, 203-259 and 413-430 were tested in (2a)PLA2 VIIB assay described above. Examples 266-412 were tested in (2b)alternative PLA2 VIIB assay described above. Examples 1-3, 5, 6, 8,11-12, 15, 17-28, 30-34, 36-52, 54-72, 74-83, 85-105, 107-119, 121, 122,124-132, 134-152, 154-167, 266, 267, 269-271, 273, 274, 279-308, 310,313, 315, 317, 320-325, 327-352, 356-361, 364, 366-373, 381-386, 388,and 390-396, 398-403, 405, 407-412, 413-420, 422, 423, and 425-429 hadat least 100 fold selectivity between human recombinant Lp-PLA₂ and PLA2VIIB.

(3) Lipoprotein-Associated Phospholipase A2 (Lp-PLA₂) Human Plasma Assay

(3a) Thio-PAF Assay

The human plasma assay utilizes a thioester analog of PAF(phosphatidylcholine), where hydrolysis yields to the formation of aphospholipid containing a free thiol group. The amount of thiol isquantitated continuously by reacting with CPM(7-diethylamino-3-(4′-maleimidylphenyl)-4-methylcoumarin), a maleimidewhich increases in fluorescence after Michael addition of thiols. Thisassay may detect the activity of Lp-PLA₂ in human plasma, as determinedby specific inhibition by Lp-PLA₂ inhibitors.

The thio-PAF assay was run as a quenched 15 μL assay. Compounds sourceplate was prepared by making 1:3 (by volume) serial dilution of thecompounds into pure DMSO on 384-well microplate. 0.01 μL of compounds oncompound source plate were transferred to 384 well Greiner 784076(black) low-volume plates by ECHO liquid dispenser. 8 μL pooled humanplasma, which was previously aliquoted and frozen, was added. Plateswere centrifuged for 10 sec at 500 rpm. After 30 minutes preincubation,2 μL of substrate solution comprising 2.5 mM 2-thio-PAF [from ethanolstock], 32 μM CPM [from a DMSO stock] and 3.2 mM NEM (N-ethylmaleimide)[made fresh daily in DMSO] in assay buffer of 50 mM HEPES, pH 7.4, 150mM NaCl, 1 mM CHAPS was added to 384 well Greiner 784076 (black)low-volume plates by BRAVO liquid handling station. After 2 mins,reaction was quenched with 5 μL of 5% aqueous trifluoroacetic acid(TFA). Plates were covered to protect from light and incubated for 40min at room temperature. Plates were read at ex: 380/em: 485 usingEnvision microplate reader. PIC50 data, curve and QC analysis wereconducted by using XLFit module in Excel.

(3b) Alternative Thio-PAF Assay

The human plasma assay utilizes the same thioester analog of PAF asdescribed in (1b) “hr ThioPAF” assay. This assay may detect the activityof Lp-PLA₂ in human plasma, as determined by specific inhibition byLp-PLA₂ inhibitors.

The thio-PAF assay was run as a quenched 20 μL assay. Compounds sourceplate was prepared by making 1:3 (by volume) serial dilution of thecompounds into pure DMSO on 96-well microplate. 5 μL of compounds oncompound source plate were transferred to 96-well Corning 3686 (black)low-volume plates by STAR+ (Hamilton) liquid dispenser. 10 μL pooledhuman plasma, which was previously aliquoted and frozen, was added.Plates were centrifuged for 30 sec at 1000 rpm. After 15 minutespreincubation at room temperature, 5 μL of substrate solution comprising2 mM 2-thio-PAF [from ethanol stock], 52 μM CPM [from a DMSO stock] and2.5 mM NEM (N-ethylmaleimide) [made fresh daily in DMSO] in assay buffer(50 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM CHAPS) was added to 96-wellCorning 3686 (black) low-volume plates. After 3 mins, reaction wasquenched with 10 μL of 5% aqueous trifluoroacetic acid (TFA). Plateswere centrifuged 30 sec at 1000 rpm, covered to protect from light andincubated for 10 min at room temperature. Plates were read at ex: 380nm/em: 485 nm using Envision plate reader (Perkin Elmer). Raw data weretransferred to Excel software and pIC50 data, curve and QC analysis wasconducted by using XL fit module in Excel.

Examples 1-265 and 413-430 were tested in the Thio-PAF assay describedin (3a) and Examples 266-274, 279-309, 310, 313, 315, 317, 320-325, 327,329-352, 356-361, 364-373, 381-388, 390-403, and 405-412 were tested inthe alternative Thio-PAF assay described in (3b). The pIC₅₀ value forall tested compounds was either reported in at least one experiment orthe average of multiple experiments.

The pIC₅₀ values in the Lp-PLA₂ human plasma assays ((3a) and 3(b)) forExamples 1-3, 5, 6, 8, 10-12, 14-60, 62-169, 171-177, 180-184, 186-189,191, 193, 195, 197, 200, 205-207, 209, 211-212, 214-216, 218-221, 225,246, 248, 249, 254-258, 262, 266-274, 279-308, 310, 313, 315, 317,320-326, 327, 329-352, 356-361, 364-373, 381-388, 390-403, 405-408,411-420, 422, 423, and 425-429 were at least 5.0.

The pIC₅₀ values in the Lp-PLA₂ human plasma assays ((3a) and 3(b)) forExamples 2, 5, 10-12, 17, 19-21, 23-26, 28, 30, 37-47, 49, 52, 54, 67,69-71, 75, 77-79, 81, 83, 85, 87, 90, 91, 107-119, 124, 125, 127-129,131, 134, 135, 139, 141, 142, 146, 149-152, 154, 162, 164-166, 221, 266,267, 269, 270, 272-274, 279-308, 310, 313, 315, 320-325, 327, 329-347,349, 351, 352, 356-360, 364, 366-373, 382-384, 386-388, 390-392,394-403, 405-408, 411, 414, 418, 423, and 426 were at least 7.0.

E. Methods of Use

The compounds of the invention are inhibitors of Lp-PLA₂. Therefore,these compounds may be used in therapy, for example, in the treatment orprevention of diseases associated with the activity of Lp-PLA₂, whichcomprises treating a subject in need thereof with a therapeuticallyeffective amount of an inhibitor of Lp-PLA₂. Accordingly, one aspect ofthe invention is directed to methods of treating or preventing diseasesassociated with the activity of Lp-PLA₂. As will be appreciated by thoseskilled in the art, a particular disease or its treatment may involveone or more underlying mechanisms associated with Lp-PLA₂ activity,including one or more of the mechanisms described herein.

In some embodiments, an inhibitor of Lp-PLA₂ according to the inventionmay be used in treating or preventing any of diseases disclosed in thefollowing published patent applications: WO96/13484, WO96/19451,WO97/02242, WO97/12963, WO97/21675, WO97/21676, WO 97/41098, WO97/41099,WO99/24420, WO00/10980, WO00/66566, WO00/66567, WO00/68208, WO01/60805,WO002/30904, WO02/30911, WO03/015786, WO03/016287, WO03/041712,WO03/042179, WO03/042206, WO03/042218, WO03/086400, WO03/87088,WO08/048867, US 2008/0103156, US 2008/0090851, US 2008/0090852,WO08/048866, WO05/003118 CA 2530816A1), WO06/063811, WO06/063813, WO2008/141176, JP 200188847, US 2008/0279846 A1, US 2010/0239565 A1, andUS 2008/0280829 A1.

In certain embodiments, the compounds of the present invention may beused to treat or prevent any diseases that involve endothelialdysfunction, for example, atherosclerosis, (e.g. peripheral vascularatherosclerosis and cerebrovascular atherosclerosis), diabetes,hypertension, angina pectoris and after ischaemia and reperfusion.

In certain embodiments, the compounds of the present invention may beused to treat or prevent any disease that involves lipid oxidation inconjunction with enzyme activity, for example, in addition to conditionssuch as atherosclerosis and diabetes, other conditions such asrheumatoid arthritis, stroke, inflammatory conditions of the brain suchas Alzheimer's Disease, various neuropsychiatric disorders such asschizophrenia, myocardial infarction, ischaemia, reperfusion injury,sepsis, and acute and chronic inflammation.

In certain embodiments, the compounds of the present invention may beused to lower the chances of having a cardiovascular event (such as aheart attack, myocardial infarction or stroke) in a patient withcoronary heart disease.

In certain embodiments, the compounds of the present invention may beused to treat or prevent diseases that involve activated monocytes,macrophages or lymphocytes, as all of these cell types express Lp-PLA₂including diseases involving activated macrophages such as M1, dendriticand/or other macrophages which generate oxidative stress. Exemplarydiseases include, but are not limited to, psoriasis, rheumatoidarthritis, wound healing, chronic obstructive pulmonary disease (COPD),liver cirrhosis, atopic dermatitis, pulmonary emphysema, chronicpancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis,multiple sclerosis, Alzheimer's disease, and autoimmune diseases such aslupus.

In other embodiments, the compounds of the invention may be used for theprimary or secondary prevention of acute coronary events, e.g. caused byatherosclerosis; adjunctive therapy in the prevention of restenosis; ordelaying the progression of diabetic or hypertensive renalinsufficiency. Prevention includes treating a subject at risk of havingsuch conditions.

In certain embodiments, the present invention provides methods oftreating or preventing a neurological disease associated with anabnormal blood brain barrier (BBB) function, inflammation, and/ormicroglia activation in a subject in need thereof. In some embodiments,the present invention provides methods of treating a neurologicaldisease associated with an abnormal blood brain barrier (BBB) function,inflammation, and/or microglia activation in a subject in need thereof.The methods comprise administering to the subject a therapeuticallyeffective amount of a compound of the present invention. In a furtherembodiment, the abnormal BBB is a permeable BBB. In yet a furtherembodiment, the disease is a neurodegeneration disease. Suchneurodegeneration diseases are, for example, but are not limited to,vascular dementia, Alzheimer's disease, Parkinson's disease andHuntington's disease. In one embodiment, the present invention providesmethods of treating or preventing disease associated with a subject withblood brain barrier (BBB) leakage. In some embodiments, the presentinvention provides methods of treating disease associated with a subjectwith blood brain barrier (BBB) leakage. Exemplary diseases include, butare not limited to, brain hemorrhage, cerebral amyloid angiopathy. Inone embodiment, the neurodegeneration disease is Alzheimer's disease. Ina certain embodiment, the neurodegeneration disease is vasculardementia. In one embodiment, the neurodegeneration disease is multiplesclerosis (MS).

In one embodiment, the compounds of the present invention may be used totreat or prevent a neurodegeneration disease in a subject. The methodscomprise administering to a subject in need thereof a compound of theinvention, e.g., as a pharmaceutical composition comprising a compoundof the invention. In one embodiment, the compounds of the presentinvention may be used to treat a neurodegeneration disease in a subject.Exemplary neurodegeneration diseases include, but are not limited to,Alzheimer's disease, vascular dementia, Parkinson's disease andHuntington's disease. In a certain embodiment, the neurodegenerationdisease described herein is associated with an abnormal blood brainbarrier. In one embodiment, the subject which is administered an agentthat inhibits the activity of Lp-PLA₂ is a human.

In one embodiment, the present invention provides methods of treating orpreventing a subject with or at risk of vascular dementia. The methodscomprise administering to the subject a compound of the invention, e.g.,as a pharmaceutical composition comprising a therapeutically effectiveamount of a compound of the present invention. In one embodiment, thepresent invention provides methods of treating a subject with or at riskof vascular dementia. In a certain embodiment, the vascular dementia isassociated with Alzheimer's disease.

In certain embodiments, the present invention provides methods ofdecreasing beta amyloid, referred to as “Ap” accumulation in the brainof a subject. The methods comprise administering to a subject in needthereof a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the present invention. In a furtherembodiment, the beta amyloid is Abeta-42.

In certain embodiments, when a subject is administered a therapeuticallyeffective amount of a compound of the present invention, the methods mayfurther comprise administering to the subject another therapeutic agentthat may be useful in treating the neurodegenerative disease for whichthe subject is being treated, or that may be a co-morbidity. In oneembodiment, the present invention provides methods of slowing ordelaying the progression of cognitive and function decline in patientswith mild Alzheimer's disease. In certain embodiment, the compounds ofthe present invention described herein may be used as an adjunct to anagent that used to provide symptomatic treatment to patients withAlzheimer's disease. For example, when the neurodegenerative disease isor is similar to Alzheimer's disease, the subject may be treated withother agents targeting Alzheimer's disease such as ARICEPT® ordonepezil, COGNEX® or tacrine, EXELON® or rivastigmine, REMINYL® orgalantamine, anti-amyloid vaccine, Abeta-lowering therapies, mentalexercise or stimulation. In certain embodiments, the present inventionprovides methods of slowing or delaying the progression of cognitive orfunction decline in a patient with mild or moderate Alzheimer's diseaseand/or cerebrovascular disease (CVD) comprise administering atherapeutically effective amount of a compound of the present inventionto the patient who has been administered an agent used to providesymptomatic treatment to Alzheimer's disease (e.g., ARICEPT® ormemantine) for 6 months or longer.

In certain embodiments, the present invention relates to methods oftreating or preventing metabolic bone diseases by administering to thesubject in need thereof a therapeutically effective amount of a compoundof the present invention. In some embodiments, the present inventionrelates to methods of treating metabolic bone diseases by administeringto the subject in need thereof a therapeutically effective amount of acompound of the present invention. Exemplary metabolic bone diseasesinclude, diseases associated with loss of bone mass and densityincluding, but are not limited to, osteoporosis and osteopenic diseases.Exemplary osteoporosis and osteopenic diseases include, but are notlimited to, bone marrow abnormalities, dyslipidemia, Paget's diseases,type II diabetes, metabolic syndrome, insulin resistance,hyperparathyroidism and related diseases. In a further embodiment, thesubject in need thereof is a human.

It is believed that methods of preventing osteoporosis and/or osteopenicdiseases described herein may be affected by inhibiting the expressionof Lp-PLA₂ and/or inhibiting the protein activity of Lp-PLA₂.Accordingly, some embodiments of the present invention provide methodsfor inhibiting Lp-PLA₂ by blocking enzyme activity. In a furtherembodiment, methods for inhibiting Lp-PLA₂ by reducing and/ordown-regulating the expression of Lp-PLA₂ RNA are provided. In a furtherembodiment, preventing and/or reducing loss of bone mass and/or loss ofbone density leads to preventing or reducing symptoms associated withmetabolic bone diseases such as osteoporosis and/or osteopenic diseases.

In certain embodiments, the methods further comprise administering to asubject in need thereof additional therapeutic agents used in thetreatment of metabolic bone diseases. For example, when the metabolicbone disease is osteoporosis additional therapeutic agents such asbisphosphates (e.g., alendronate, ibandromate, risedronate, calcitonin,raloxifene), a selective estrogen modulator (SERM), estrogen therapy,hormone replacement therapy (ET/HRT) and teriparatide may be used.

One aspect of the present invention provides methods for treating and/orpreventing ocular diseases by administering a therapeutically effectiveamount of a compound of the present invention. In some embodiments, thepresent invention provides methods for treating ocular diseases byadministering a therapeutically effective amount of a compound of thepresent invention. Ocular diseases applicable in the present inventionmay be associated with the breakdown of the inner blood-retinal barrier(iBRB). Exemplary ocular diseases relate to diabetic ocular, whichinclude macular edema, diabetic retinopathy, posterior uveitis, retinalvein occlusion and the like. Further, in one embodiment, the presentinvention relates to methods for treating ocular diseases byadministering a compound of the present invention to inhibit Lp-PLA₂.Exemplary ocular diseases include, but are not limited to, centralretinal vein occlusion, branched retinal vein occlusion, Irvine-Gasssyndrome (post cataract and post-surgical), retinitis pigmentosa, parsplanitis, birdshot retinochoroidopathy, epiretinal membrane, choroidaltumors, cystic macular edema, parafoveal telengiectasis, tractionalmaculopathies, vitreomacular traction syndromes, retinal detachment,neuroretinitis, idiopathic macular edema, and the like. More details ofusing Lp-PLA₂ inhibitor to treat eye diseases are provided inWO2012/080497, which is incorporated by reference herein.

Further, some embodiments of the present invention provide methods fortreating or preventing diabetic macular edema in a subject. In someembodiments, the present invention provides methods for treatingdiabetic macular edema in a subject. The method comprises administeringto a subject in need thereof a therapeutically effective amount of acompound of the present invention.

In certain embodiments, the present invention provides methods oftreating or preventing a subject with or at risk of macular edema. Insome embodiments, the present invention provides methods of treating asubject with or at risk of macular edema. The methods compriseadministering to the subject a therapeutically effective amount of acompound of the present invention. In a further embodiment, the macularedema is associated with diabetic ocular disease, for example, diabeticmacular edema or diabetic retinopathy. In yet a further embodiment, themacular edema is associated with posterior uveitis.

In certain embodiments, the present invention provides methods oftreating or preventing glaucoma or macular degeneration. In someembodiments, the present invention provides methods of treating glaucomaor macular degeneration. The methods comprise administering to thesubject a therapeutically effective amount of a compound of the presentinvention.

In one embodiment, the present invention provides methods of treating orpreventing a disease associated with the breakdown of the innerblood-retinal barrier in a subject in need thereof. In one embodiment,the present invention provides methods of treating a disease associatedwith the breakdown of the inner blood-retinal barrier in a subject inneed thereof. The methods comprise administering to the subject atherapeutically effective amount of a compound of the present invention.

In one embodiment, systemic inflammatory diseases such as, juvenilerheumatoid arthritis, inflammatory bowel disease, Kawasaki disease,multiple sclerosis, sarcoidosis, polyarteritis, psoriatic arthritis,reactive arthritis, systemic lupus erythematosus, Vogt-Koyanagi-Haradasyndrome, Lyme disease, Bechet's disease, ankylosing sponsylitis,chronic granulomatous disease, enthesitis, may be the underlying causeof posterior uveitis affecting the retina, and which can result inmacula edema. The present invention relates to methods for treating orpreventing posterior uveitis or any of these systemic inflammatorydiseases by administering a therapeutically effective amount of acompound of the present invention. In one embodiment, the presentinvention provides methods for treating posterior uveitis or any ofthese systemic inflammatory diseases by administering a therapeuticallyeffective amount of a compound of the present invention.

It is believed that Lp-PLA₂ inhibitors may have beneficial effects ondiseases associated with M1/M2 macrophage polarization. The belief isbased on the following studies. A study was carried out by GSK toinvestigate the relationship between M1/M2 macrophage polarization anddifferent diseases. 94 human markers described in Martinez F O et al.,which distinguished M1 and M2 phenotypes was used against a GSKsubscribed GeneLogic database. (See Martinez F O et al. (2006) J Immunol177, 7303-7311.) The Connectivity Map methodology described in Lamb J etal. was used to identify the fraction of samples in each disease statehaving expression characteristics consistent with a M1-favoring orM2-favoring macrophage population. (See Lamb J et al. (2006) Science313, 1929-1935) (PMID 17008526)). The study showed that liver cirrhosis,skin psoriasis, atopic dermatitis, pulmonary emphysema, chronicpancreatitis, chronic gastritis, and aortic aneurysm have M1/M2imbalance.

A further study was carried out to study the impact of Lp-PLA₂inhibitors on modulating M1/M2 imbalance. In this study, rats wereinduced to develop experimental autoimmune encephalomyelitis (EAE) byimmunization with myelin basic protein (MBP) antigen and treated with aknown Lp-PLA₂ inhibitor:5-((9-Methoxy-4-oxo-6,7-dihydro-4H-pyrimido[6,1-a]isoquinolin-2-yl)oxy)-2-(3-(trifluoromethyl)phenoxy)benzonitrile(See PCT application no. PCT/CN2011/001597). In this preventivetreatment model, the compound was administered at day 0 (day ofimmunization) and continued to administer until day 22. The study lastedfor 25 days. Rats were subsequently monitored for symptoms of EAE. Ratswere immunized with MBP to develop EAE and symptoms were monitoreddaily. Plasma Lp-PLA₂ activity, OxLDL, and LysoPC concentration weredetermined at different time points through the course of EAE. Theresults showed that plasma Lp-PLA₂ activity, OxLDL, and LysoPCconcentrations increased as the clinical EAE disease progressed in themodel, which indicates that they played a role in the pathologydevelopment. Lp-PLA₂ inhibitor treatment led to reduction in clinicaldisease associated with decreased Lp-PLA₂ activity and LysoPC levels inrat EAE plasma. Hence, inhibition of Lp-PLA₂ activity is beneficial inameliorating disease in the rat EAE model.

Ex vivo analysis of proinflammatory (M1) and anti-inflammatory (M2)markers in control and compound treated EAE rats. Splenic macrophageswere harvested at day 13 post MBP-immunization and assayed forexpression of a variety of markers by realtime PCR. CNS infiltratingcells were harvested and macrophages were analyzed for expression of M1and M2 markers by realtime PCR. Treatment with compound resulted in thedecrease in M1 markers and increase in M2 markers, which potentiallyindicated the possibility of anti-inflammation and tissue repair.

Therefore, in certain embodiments, the present invention providesmethods of treating or preventing disease associated with macrophagepolarization, for example, M1/M2 macrophage polarization. In someembodiments, the present invention provides methods of treating diseaseassociated with macrophage polarization, for example, M1/M2 macrophagepolarization. Exemplary diseases associated with macrophage polarizationinclude, but are not limited to, liver cirrhosis, skin psoriasis, atopicdermatitis, pulmonary emphysema, chronic pancreatitis, chronicgastritis, aortic aneurysm, atherosclerosis, multiple sclerosis,amyotrophic lateral sclerosis (ALS), ischemic cardiomyopathy, chronicheart failure post myocardial infarction (MI) and other autoimmunediseases that are associated with macrophage polarization.

Treatment and or prevention of a disease associated with Lp-PLA₂activity may be achieved using a compound of this invention as amonotherapy, or in dual or multiple combination therapy. For example,the compounds of the present invention may be used to treat or preventthe disease described herein in combination with ananti-hyperlipidaemic, anti-atherosclerotic, anti-diabetic, anti-anginal,anti-inflammatory, or anti-hypertension agent or an agent for loweringLipoprotein (a) (Lp(a)). Examples of the above include, but are notlimited to, cholesterol synthesis inhibitors such as statins,antioxidants such as probucol, insulin sensitizers, calcium channelantagonists, and anti-inflammatory drugs such as non-steroidalanti-inflammatory Drugs (NSAIDs). Examples of agents for lowering Lp(a)include the aminophosphonates described in WO 97/02037, WO 98/28310, WO98/28311 and WO 98/28312. In one embodiment, the compounds of thepresent invention may be used with one or more statins. The statins area well-known class of cholesterol lowering agents and includeatorvastatin, simvarstatin, pravastatin, cerivastatin, fluvastatin,lovastatin and rosuvastatin. In a certain embodiment, the compounds ofthe present invention may be used with an anti-diabetic agent or aninsulin sensitizer. In one embodiment, a compound of the presentinvention may be used with PPAR gamma activators, for instance GI262570(GlaxoSmithKline) and the glitazone class of compounds such asrosiglitazone, troglitazone and pioglitazone. Such agents may beadministered in therapeutically effective amounts, e.g., as is known inthe art, or lesser or greater amounts than known in the art providedthat the amount administered is therapeutically effective.

Combination therapy includes administration of the therapeutic agents inseparate dosage forms or together in a single dosage form. Combinationtherapy may involve simultaneous administration or separateadministration of the therapeutic agents, which may be substantiallysimultaneous or substantially separate administration. Typically,combination therapy will involve administration of each agent such thattherapeutically effective amounts of each agent are present in thesubject's body in at least an overlapping period.

One aspect of the present invention provides the use of a compound ofthe present invention for the preparation of a medicament for carryingout a method described herein.

In some embodiments, the present invention provides the use of acompound of the present invention for the preparation of a medicamentfor treating or preventing diseases associated with the activity ofLp-PLA₂.

In some embodiments, it provides the use of a compound of the presentinvention for preparation of a medicament for treating or preventing anyof diseases disclosed in the following published patent applications:WO96/13484, WO96/19451, WO97/02242, WO97/12963, WO97/21675, WO97/21676,WO 97/41098, WO97/41099, WO99/24420, WO00/10980, WO00/66566, WO00/66567,WO00/68208, WO01/60805, WO002/30904, WO02/30911, WO03/015786,WO03/016287, WO03/041712, WO03/042179, WO03/042206, WO03/042218,WO03/086400, WO03/87088, WO08/048867, US 2008/0103156, US 2008/0090851,US 2008/0090852, WO08/048866, WO05/003118 CA 2530816A1), WO06/063811,WO06/063813, WO 2008/141176, JP 200188847, US 2008/0279846 A1, US2010/0239565 A1, and US 2008/0280829 A1.

In certain embodiments, the present invention provides the use of acompound of the present invention for the preparation of a medicamentfor treating or preventing any diseases that involve endothelialdysfunction, for example, atherosclerosis, (e.g. peripheral vascularatherosclerosis and cerebrovascular atherosclerosis), diabetes,hypertension, angina pectoris and after ischaemia and reperfusion.

In certain embodiments, the present invention provides the use of acompound of the present invention for the preparation of a medicamentfor treating or preventing any disease that involves lipid oxidation inconjunction with enzyme activity, for example, in addition to conditionssuch as atherosclerosis and diabetes, other conditions such asrheumatoid arthritis, stroke, inflammatory conditions of the brain suchas Alzheimer's Disease, various neuropsychiatric disorders such asschizophrenia, myocardial infarction, ischaemia, reperfusion injury,sepsis, and acute and chronic inflammation.

In certain embodiments, the present invention provides the use of acompound of the present invention for the preparation of a medicamentfor lowering the chances of having a cardiovascular event (such as aheart attack, myocardial infarction or stroke) in a patient withcoronary heart disease.

In certain embodiments, the present invention provides the use of acompound of the present invention for the preparation of a medicamentfor treating or preventing diseases that involve activated monocytes,macrophages or lymphocytes, as all of these cell types express Lp-PLA₂including diseases involving activated macrophages such as M1, dendriticand/or other macrophages which generate oxidative stress. Exemplarydiseases include, but are not limited to, psoriasis, rheumatoidarthritis, wound healing, chronic obstructive pulmonary disease (COPD),liver cirrhosis, atopic dermatitis, pulmonary emphysema, chronicpancreatitis, chronic gastritis, aortic aneurysm, atherosclerosis,multiple sclerosis, Alzheimer's disease, and autoimmune diseases such aslupus.

In other embodiments, the present invention provides the use of acompound of the present invention for the preparation of a medicamentfor the primary or secondary prevention of acute coronary events, e.g.caused by atherosclerosis; adjunctive therapy in the prevention ofrestenosis; or delaying the progression of diabetic or hypertensiverenal insufficiency. Prevention includes treating a subject at risk ofhaving such conditions.

In certain embodiments, the present invention provides the use of acompound of the present invention for the preparation of a medicamentfor treating or preventing a neurological disease associated with anabnormal blood brain barrier (BBB) function, inflammation, and/ormicroglia activation in a subject in need thereof. In some embodiments,the present invention provides the use of a compound of the presentinvention for the preparation of a medicament for treating aneurological disease associated with an abnormal blood brain barrier(BBB) function, inflammation, and/or microglia activation in a subjectin need thereof. In a further embodiment, the abnormal BBB is apermeable BBB. In yet a further embodiment, the disease is aneurodegeneration disease. Such neurodegeneration diseases are, forexample, but are not limited to, vascular dementia, Alzheimer's disease,Parkinson's disease and Huntington's disease. In one embodiment, thepresent invention provides use of a compound of the present inventionfor the preparation of a medicament for treating or preventing diseaseassociated with a subject with blood brain barrier (BBB) leakage. Insome embodiments, the present invention provides the use of a compoundof the present invention for the preparation of a medicament fortreating disease associated with a subject with blood brain barrier(BBB) leakage. Exemplary diseases include, but are not limited to, brainhemorrhage, cerebral amyloid angiopathy. In one embodiment, theneurodegeneration disease is Alzheimer's disease. In a certainembodiment, the neurodegeneration disease is vascular dementia. In oneembodiment, the neurodegeneration disease is multiple sclerosis (MS).

In one embodiment, the present invention provides the use of a compoundof the present invention for the preparation of a medicament fortreating or preventing a neurodegeneration disease in a subject. In oneembodiment, the present invention provides the use of a compound of thepresent invention for the preparation of a medicament for treating aneurodegeneration disease in a subject. Exemplary neurodegenerationdiseases include, but are not limited to, Alzheimer's disease, vasculardementia, Parkinson's disease and Huntington's disease. In a certainembodiment, the neurodegeneration disease described herein is associatedwith an abnormal blood brain barrier.

In one embodiment, the present invention provides the use of a compoundof the present invention for the preparation of a medicament fortreating or preventing a subject with or at risk of vascular dementia.In one embodiment, the present invention provides the use of a compoundof the present invention for the preparation of a medicament fortreating a subject with or at risk of vascular dementia. In a certainembodiment, the vascular dementia is associated with Alzheimer'sdisease.

In certain embodiments, the present invention provides the use of acompound of the present invention for the preparation of a medicamentfor decreasing beta amyloid, referred to as “Aβ” accumulation in thebrain of a subject. In a further embodiment, the beta amyloid isAbeta-42.

In one embodiment, the present invention provides the use of a compoundof the present invention for the preparation of a medicament for slowingor delaying the progression of cognitive function decline in patientswith mild Alzheimer's disease. In certain embodiment, the presentinvention provides the use of a compound of the present invention forthe preparation of a medicament as an adjunct to an agent that used toprovide symptomatic treatment to patients with Alzheimer's disease. Forexample, when the neurodegenerative disease is or is similar toAlzheimer's disease, the subject may be treated with other agentstargeting Alzheimer's disease such as ARICEPT® or donepezil, COGNEX® ortacrine, EXELON® or rivastigmine, REMINYL® or galantamine, anti-amyloidvaccine, Abeta-lowering therapies, mental exercise or stimulation. Incertain embodiments, the present invention provides the use of acompound of the present invention for the preparation of a medicamentfor slowing or delaying the progression of cognitive function decline ina patient with mild or moderate Alzheimer's disease and/orcerebrovascular disease (CVD), wherein the patient who has beenadministered an agent used to provide symptomatic treatment toAlzheimer's disease (e.g., ARICEPT® or memantine) for 6 months orlonger. In certain embodiments, the present invention provides the useof a compound of the present invention for the preparation of amedicament for slowing or delaying the progression of cognitive functiondecline in a patient with mild or moderate Alzheimer's disease andcerebral small vessel disease (SVD), wherein the patient who has beenadministered an agent used to provide symptomatic treatment toAlzheimer's disease (e.g., ARICEPT® or memantine) for 6 months orlonger.

In certain embodiments, the present invention provides the use of acompound of the present invention for the preparation of a medicamentfor treating or preventing metabolic bone diseases. In some embodiments,the present invention provides the use of a compound of the presentinvention for the preparation of a medicament for treating metabolicbone diseases. Exemplary metabolic bone diseases include, diseasesassociated with loss of bone mass and density including, but are notlimited to, osteoporosis and osteopenic diseases. Exemplary osteoporosisand osteopenic diseases include, but are not limited to, bone marrowabnormalities, dyslipidemia, Paget's diseases, type II diabetes,metabolic syndrome, insulin resistance, hyperparathyroidism and relateddiseases. In a further embodiment, the present invention provides theuse of a compound of the present invention for the preparation of amedicament for preventing and/or reducing loss of bone mass and/or lossof bone density leads to preventing or reducing symptoms associated withmetabolic bone diseases such as osteoporosis and/or osteopenic diseases.

In certain embodiments, the present invention provides the use of acompound of the present invention for the preparation of a medicamentfor treating metabolic bone diseases, wherein the medicament is usedwith additional therapeutic agents used in the treatment of metabolicbone diseases. For example, when the metabolic bone disease isosteoporosis additional therapeutic agents such as bisphosphates (e.g.,alendronate, ibandromate, risedronate, calcitonin, raloxifene), aselective estrogen modulator (SERM), estrogen therapy, hormonereplacement therapy (ET/HRT) and teriparatide may be used.

One aspect of the present invention provides the use of a compound ofthe present invention for the preparation of a medicament for treatingand/or preventing ocular diseases. In some embodiments, the presentinvention provides the use of a compound of the present invention forthe preparation of a medicament for treating ocular diseases. Oculardiseases applicable in the present invention may be associated with thebreakdown of the inner blood-retinal barrier (iBRB). Exemplary oculardiseases relate to diabetic ocular, which include macular edema,diabetic retinopathy, posterior uveitis, retinal vein occlusion and thelike. More ocular diseases include, but are not limited to, centralretinal vein occlusion, branched retinal vein occlusion, Irvine-Gasssyndrome (post cataract and post-surgical), retinitis pigmentosa, parsplanitis, birdshot retinochoroidopathy, epiretinal membrane, choroidaltumors, cystic macular edema, parafoveal telengiectasis, tractionalmaculopathies, vitreomacular traction syndromes, retinal detachment,neuroretinitis, idiopathic macular edema, and the like. More details ofusing Lp-PLA₂ inhibitor to treat eye diseases are provided inWO2012/080497, which is incorporated by reference herein.

Further, some embodiments of the present invention provide the use of acompound of the present invention for the preparation of a medicamentfor treating or preventing diabetic macular edema in a subject. In someembodiments, the present invention provides the use of a compound of thepresent invention for treating diabetic macular edema in a subject.

In certain embodiments, the present invention provides the use of acompound of the present invention for the preparation of a medicamentfor treating or preventing a subject with or at risk of macular edema.In some embodiments, the present invention provides the use of acompound of the present invention for the preparation of a medicamentfor treating a subject with or at risk of macular edema. In a furtherembodiment, the macular edema is associated with diabetic oculardisease, for example, diabetic macular edema or diabetic retinopathy. Inyet a further embodiment, the macular edema is associated with posterioruveitis.

In certain embodiments, the present invention provides the use of acompound of the present invention for the preparation of a medicamentfor treating or preventing glaucoma or macular degeneration. In someembodiments, the present invention provides the use of a compound of thepresent invention for the preparation of a medicament for treatingglaucoma or macular degeneration.

In one embodiment, the present invention provides the use of a compoundof the present invention for the preparation of a medicament fortreating or preventing a disease associated with the breakdown of theinner blood-retinal barrier in a subject in need thereof. In oneembodiment, the present invention provides the use of a compound of thepresent invention for the preparation of a medicament for treating adisease associated with the breakdown of the inner blood-retinal barrierin a subject in need thereof.

In one embodiment, systemic inflammatory diseases such as, juvenilerheumatoid arthritis, inflammatory bowel disease, Kawasaki disease,multiple sclerosis, sarcoidosis, polyarteritis, psoriatic arthritis,reactive arthritis, systemic lupus erythematosus, Vogt-Koyanagi-Haradasyndrome, Lyme disease, Bechet's disease, ankylosing sponsylitis,chronic granulomatous disease, enthesitis, may be the underlying causeof posterior uveitis affecting the retina, and which can result inmacula edema. In one embodiment, the present invention provides the useof a compound of the present invention for the preparation of amedicament for treating posterior uveitis or any of these systemicinflammatory diseases.

In certain embodiments, the present invention provides the use of acompound of the present invention for the preparation of a medicamentfor treating or preventing disease associated with macrophagepolarization, for example, M1/M2 macrophage polarization. In someembodiments, the present invention provides the use of a compound of thepresent invention for the preparation of a medicament for treatingdisease associated with macrophage polarization, for example, M1/M2macrophage polarization. Exemplary diseases associated with macrophagepolarization include, but are not limited to, liver cirrhosis, skinpsoriasis, atopic dermatitis, pulmonary emphysema, chronic pancreatitis,chronic gastritis, aortic aneurysm, atherosclerosis, multiple sclerosis,amyotrophic lateral sclerosis (ALS), ischemic cardiomyopathy, chronicheart failure post myocardial infarction (MI) and other autoimmunediseases that are associated with macrophage polarization.

Another aspect of the present invention provides a compound of thepresent invention for use in carrying out methods of treatment orprevention described herein. A further aspect of the present inventionprovides a compound described herein or a pharmaceutically acceptablesalt thereof, for use in therapy.

In some embodiments, the present invention provides a compound of thepresent invention for use in treating or preventing diseases associatedwith the activity of Lp-PLA₂.

In some embodiments, the present invention provides a compound of thepresent invention for use in treating or preventing any of diseasesdisclosed in the following published patent applications: WO96/13484,WO96/19451, WO97/02242, WO97/12963, WO97/21675, WO97/21676, WO 97/41098,WO97/41099, WO99/24420, WO00/10980, WO00/66566, WO00/66567, WO00/68208,WO01/60805, WO002/30904, WO02/30911, WO03/015786, WO03/016287,WO03/041712, WO03/042179, WO03/042206, WO03/042218, WO03/086400,WO03/87088, WO08/048867, US 2008/0103156, US 2008/0090851, US2008/0090852, WO08/048866, WO05/003118 CA 2530816A1), WO06/063811,WO006/063813, WO 2008/141176, JP 200188847, US 2008/0279846 A1, US2010/0239565 A1, and US 2008/0280829 A1.

In certain embodiments, the present invention provides a compound of thepresent invention for use in treating or preventing any diseases thatinvolve endothelial dysfunction, for example, atherosclerosis, (e.g.peripheral vascular atherosclerosis and cerebrovascularatherosclerosis), diabetes, hypertension, angina pectoris and afterischaemia and reperfusion.

In certain embodiments, the present invention provides a compound of thepresent invention for use in treating or preventing any disease thatinvolves lipid oxidation in conjunction with enzyme activity, forexample, in addition to conditions such as atherosclerosis and diabetes,other conditions such as rheumatoid arthritis, stroke, inflammatoryconditions of the brain such as Alzheimer's Disease, variousneuropsychiatric disorders such as schizophrenia, myocardial infarction,ischaemia, reperfusion injury, sepsis, and acute and chronicinflammation.

In certain embodiments, the present invention provides a compound of thepresent invention for use in lowering the chances of having acardiovascular event (such as a heart attack, myocardial infarction orstroke) in a patient with coronary heart disease.

In certain embodiments, the present invention provides a compound of thepresent invention for use in treating or preventing diseases thatinvolve activated monocytes, macrophages or lymphocytes, as all of thesecell types express Lp-PLA₂ including diseases involving activatedmacrophages such as M1, dendritic and/or other macrophages whichgenerate oxidative stress. Exemplary diseases include, but are notlimited to, psoriasis, rheumatoid arthritis, wound healing, chronicobstructive pulmonary disease (COPD), liver cirrhosis, atopicdermatitis, pulmonary emphysema, chronic pancreatitis, chronicgastritis, aortic aneurysm, atherosclerosis, multiple sclerosis,Alzheimer's disease, and autoimmune diseases such as lupus.

In other embodiments, the present invention provides a compound of thepresent invention for use in the primary or secondary prevention ofacute coronary events, e.g. caused by atherosclerosis; adjunctivetherapy in the prevention of restenosis; or delaying the progression ofdiabetic or hypertensive renal insufficiency. Prevention includestreating a subject at risk of having such conditions.

In certain embodiments, the present invention provides a compound of thepresent invention for use in treating or preventing a neurologicaldisease associated with an abnormal blood brain barrier (BBB) function,inflammation, and/or microglia activation in a subject in need thereof.In some embodiments, the present invention provides a compound of thepresent invention for use in treating a neurological disease associatedwith an abnormal blood brain barrier (BBB) function, inflammation,and/or microglia activation. In a further embodiment, the abnormal BBBis a permeable BBB. In yet a further embodiment, the disease is aneurodegeneration disease. Such neurodegeneration diseases are, forexample, but are not limited to, vascular dementia, Alzheimer's disease,Parkinson's disease and Huntington's disease. In one embodiment, thepresent invention provides a compound of the present invention for usein treating or preventing disease associated with a subject with bloodbrain barrier (BBB) leakage. In some embodiments, the present inventionprovides a compound of the present invention for use in treating diseaseassociated with a subject with blood brain barrier (BBB) leakage.Exemplary diseases include, but are not limited to, brain hemorrhage,cerebral amyloid angiopathy. In one embodiment, the neurodegenerationdisease is Alzheimer's disease. In a certain embodiment, theneurodegeneration disease is vascular dementia. In one embodiment, theneurodegeneration disease is multiple sclerosis (MS).

In one embodiment, the present invention provides a compound of thepresent invention for use in treating or preventing a neurodegenerationdisease in a subject. In one embodiment, the present invention providesa compound of the present invention for use in treating aneurodegeneration disease in a subject. Exemplary neurodegenerationdiseases include, but are not limited to, Alzheimer's disease, vasculardementia, Parkinson's disease and Huntington's disease. In a certainembodiment, the neurodegeneration disease described herein is associatedwith an abnormal blood brain barrier.

In one embodiment, the present invention provides a compound of thepresent invention for use in treating or preventing a subject with or atrisk of vascular dementia. In one embodiment, the present inventionprovides a compound of the present invention for use in treating asubject with or at risk of vascular dementia. In a certain embodiment,the vascular dementia is associated with Alzheimer's disease.

In certain embodiments, the present invention provides a compound of thepresent invention for use in decreasing beta amyloid, referred to as“Aβ” accumulation in the brain of a subject. In a further embodiment,the beta amyloid is Abeta-42.

In one embodiment, the present invention provides a compound of thepresent invention for use in slowing or delaying the progression ofcognitive function decline in patients with mild Alzheimer's disease. Incertain embodiment, the present invention provides a compound of thepresent invention for use as an adjunct to an agent that used to providesymptomatic treatment to patients with Alzheimer's disease. For example,when the neurodegenerative disease is or is similar to Alzheimer'sdisease, the subject may be treated with other agents targetingAlzheimer's disease such as ARICEPT® or donepezil, COGNEX® or tacrine,EXELON® or rivastigmine, REMINYL® or galantamine, anti-amyloid vaccine,Abeta-lowering therapies, mental exercise or stimulation. In certainembodiments, the present invention provides a compound of the presentinvention for use in slowing or delaying the progression of cognitivefunction decline in a patient with mild or moderate Alzheimer's diseaseand/or cerebrovascular disease (CVD), wherein the patient who has beenadministered an agent used to provide symptomatic treatment toAlzheimer's disease (e.g., ARICEPT® or memantine) for 6 months orlonger. In certain embodiments, the present invention provides acompound of the present invention for use in slowing or delaying theprogression of cognitive function decline in a patient with mild ormoderate Alzheimer's disease and cerebral small vessel disease (SVD),wherein the patient who has been administered an agent used to providesymptomatic treatment to Alzheimer's disease (e.g., ARICEPT® ormemantine) for 6 months or longer.

In certain embodiments, the present invention provides a compound of thepresent invention for use in treating or preventing metabolic bonediseases. In some embodiments, the present invention provides a compoundof the present invention for use in treating metabolic bone diseases.Exemplary metabolic bone diseases include, diseases associated with lossof bone mass and density including, but are not limited to, osteoporosisand osteopenic diseases. Exemplary osteoporosis and osteopenic diseasesinclude, but are not limited to, bone marrow abnormalities,dyslipidemia, Paget's diseases, type II diabetes, metabolic syndrome,insulin resistance, hyperparathyroidism and related diseases. In afurther embodiment, the present invention provides a compound of thepresent invention for use in preventing and/or reducing loss of bonemass and/or loss of bone density leads to preventing or reducingsymptoms associated with metabolic bone diseases such as osteoporosisand/or osteopenic diseases.

In certain embodiments, the present invention provides a compound of thepresent invention for use in treating metabolic bone diseases, whereinthe medicament is used with additional therapeutic agents used in thetreatment of metabolic bone diseases. For example, when the metabolicbone disease is osteoporosis additional therapeutic agents such asbisphosphates (e.g., alendronate, ibandromate, risedronate, calcitonin,raloxifene), a selective estrogen modulator (SERM), estrogen therapy,hormone replacement therapy (ET/HRT) and teriparatide may be used.

One aspect of the present invention provides a compound of the presentinvention for use the use in treating and/or preventing ocular diseases.In some embodiments, the present invention provides a compound of thepresent invention for use in treating ocular diseases. Ocular diseasesapplicable in the present invention may be associated with the breakdownof the inner blood-retinal barrier (iBRB). Exemplary ocular diseasesrelate to diabetic ocular, which include macular edema, diabeticretinopathy, posterior uveitis, retinal vein occlusion and the like.More ocular diseases include, but are not limited to, central retinalvein occlusion, branched retinal vein occlusion, Irvine-Gass syndrome(post cataract and post-surgical), retinitis pigmentosa, pars planitis,birdshot retinochoroidopathy, epiretinal membrane, choroidal tumors,cystic macular edema, parafoveal telengiectasis, tractionalmaculopathies, vitreomacular traction syndromes, retinal detachment,neuroretinitis, idiopathic macular edema, and the like. More details ofusing Lp-PLA₂ inhibitor to treat eye diseases are provided inWO2012/080497, which is incorporated by reference herein.

Further, some embodiments of the present invention provide a compound ofthe present invention for use in treating or preventing diabetic macularedema in a subject. In some embodiments, the present invention providesa compound of the present invention for use in treating diabetic macularedema in a subject.

In certain embodiments, the present invention provides a compound of thepresent invention for use in treating or preventing a subject with or atrisk of macular edema. In some embodiments, the present inventionprovides a compound of the present invention for use in treating asubject with or at risk of macular edema. In a further embodiment, themacular edema is associated with diabetic ocular disease, for example,diabetic macular edema or diabetic retinopathy. In yet a furtherembodiment, the macular edema is associated with posterior uveitis.

In certain embodiments, the present invention provides a compound of thepresent invention for use in treating or preventing glaucoma or maculardegeneration. In some embodiments, the present invention provides acompound of the present invention for use in treating glaucoma ormacular degeneration.

In one embodiment, the present invention provides a compound of thepresent invention for use in treating or preventing a disease associatedwith the breakdown of the inner blood-retinal barrier in a subject inneed thereof. In one embodiment, the present invention provides acompound of the present invention for use in treating a diseaseassociated with the breakdown of the inner blood-retinal barrier in asubject in need thereof.

In one embodiment, systemic inflammatory diseases such as, juvenilerheumatoid arthritis, inflammatory bowel disease, Kawasaki disease,multiple sclerosis, sarcoidosis, polyarteritis, psoriatic arthritis,reactive arthritis, systemic lupus erythematosus, Vogt-Koyanagi-Haradasyndrome, Lyme disease, Bechet's disease, ankylosing sponsylitis,chronic granulomatous disease, enthesitis, may be the underlying causeof posterior uveitis affecting the retina, and which can result inmacula edema. In one embodiment, the present invention provides acompound of the present invention for use in treating posterior uveitisor any of these systemic inflammatory diseases.

In certain embodiments, the present invention provides a compound of thepresent invention for use in treating or preventing disease associatedwith macrophage polarization, for example, M1/M2 macrophagepolarization. In some embodiments, the present invention provides theuse of a compound of the present invention for the preparation of amedicament for treating disease associated with macrophage polarization,for example, M1/M2 macrophage polarization. Exemplary diseasesassociated with macrophage polarization include, but are not limited to,liver cirrhosis, skin psoriasis, atopic dermatitis, pulmonary emphysema,chronic pancreatitis, chronic gastritis, aortic aneurysm,atherosclerosis, multiple sclerosis, amyotrophic lateral sclerosis(ALS), ischemic cardiomyopathy, chronic heart failure post myocardialinfarction (MI) and other autoimmune diseases that are associated withmacrophage polarization.

F. Composition

The compounds of the present invention may be formulated intopharmaceutical compositions prior to administration to a subject.Accordingly, one aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of the invention and apharmaceutically acceptable excipient. In accordance with another aspectof the invention, a process is provided for the preparation of apharmaceutical composition including admixing a compound of the abovereferenced formulas or salts thereof, solvates etc thereof, with one ormore pharmaceutically acceptable excipient.

Pharmaceutical compositions may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, for example, 0.1 mg, 0.5 mg, or 1 mg to 50 mg,100 mg, 200 mg, 250 mg, 500 mg, 750 mg or 1 g of a compound of thepresent invention, depending on the condition being treated, the routeof administration and the age, weight and condition of the subject, orpharmaceutical compositions may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose. Inother embodiments, the unit dosage compositions are those containing adaily dose or sub-dose as described herein, or an appropriate fractionthereof, of an active ingredient. Furthermore, such pharmaceuticalcompositions may be prepared by any of the methods well-known to oneskilled in the art.

A therapeutically effective amount of a compound of the presentinvention will depend upon a number of factors including, for example,the age and weight of the intended recipient, the precise conditionrequiring treatment and its severity, the nature of the formulation, andthe route of administration, and will ultimately be at the discretion ofthe attendant prescribing the medication. However, a therapeuticallyeffective amount of a compound of present invention for the treatment ofthe disease described herein will generally be in the range of 0.1 to100 mg/kg body weight of recipient per day and more usually in the rangeof 1 to 10 mg/kg body weight per day. Thus, for example, for a 70 kgadult mammal, the actual amount per day would usually be from 70 to 700mg and this amount may be given in a single dose per day or in a numberof sub-doses per day as such as two, three, four, five or six doses perday. Or the dosing can be done intermittently, such as once every otherday, once a week or once a month. It is envisaged that similar dosageswould be appropriate for treatment of the other conditions referred toabove.

The pharmaceutical compositions of the invention may contain one or morecompounds of the invention. In some embodiments, the pharmaceuticalcompositions may contain more than one compound of the invention. Forexample, in some embodiments, the pharmaceutical compositions maycontain two or more compounds of the invention. In addition, thepharmaceutical compositions may optionally further comprise one or moreadditional pharmaceutically active compounds.

As used herein, “pharmaceutically acceptable excipient” means apharmaceutically acceptable material, composition or vehicle involved ingiving form or consistency to the pharmaceutical composition. Eachexcipient may be compatible with the other ingredients of thepharmaceutical composition when commingled such that interactions whichwould substantially reduce the efficacy of the compound of the inventionwhen administered to a subject and interactions which would result inpharmaceutical compositions that are not pharmaceutically acceptable areavoided.

The compounds of the invention and the pharmaceutically acceptableexcipient or excipients may be formulated into a dosage form adapted foradministration to the subject by the desired route of administration.For example, dosage forms include those adapted for (1) oraladministration (including buccal or sublingual) such as tablets,capsules, caplets, pills, troches, powders, syrups, elixers,suspensions, solutions, emulsions, sachets, and cachets; (2) parenteraladministration (including subcutaneous, intramuscular, intravenous orintradermal) such as sterile solutions, suspensions, and powders forreconstitution; (3) transdermal administration such as transdermalpatches; (4) rectal administration such as suppositories; (5) nasalinhalation such as dry powders, aerosols, suspensions, and solutions;and (6) topical administration (including buccal, sublingual ortransdermal) such as creams, ointments, lotions, solutions, pastes,sprays, foams, and gels. Such compositions may be prepared by anymethods known in the art of pharmacy, for example by bringing intoassociation a compound of the above referenced formulas with thecarrier(s) or excipient(s).

Pharmaceutical compositions adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

Suitable pharmaceutically acceptable excipients may vary depending uponthe particular dosage form chosen. In addition, suitablepharmaceutically acceptable excipients may be chosen for a particularfunction that they may serve in the composition. For example, certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of uniform dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate the production of stable dosage forms. Certainpharmaceutically acceptable excipients may be chosen for their abilityto facilitate carrying or transporting the compound or compounds of theinvention once administered to the subject from an organ, or a portionof the body, to another organ, or a portion of the body. Certainpharmaceutically acceptable excipients may be chosen for their abilityto enhance patient compliance.

Suitable pharmaceutically acceptable excipients include the followingtypes of excipients: diluents, fillers, binders, disintegrants,lubricants, glidants, granulating agents, coating agents, wettingagents, solvents, co-solvents, suspending agents, emulsifiers,sweeteners, flavoring agents, flavor masking agents, coloring agents,anticaking agents, hemectants, chelating agents, plasticizers, viscosityincreasing agents, antioxidants, preservatives, stabilizers,surfactants, and buffering agents. The skilled artisan will appreciatethat certain pharmaceutically acceptable excipients may serve more thanone function and may serve alternative functions depending on how muchthe excipient is present in the formulation and what other ingredientsare present in the formulation.

Skilled artisans possess the knowledge and skill in the art to enablethem to select suitable pharmaceutically acceptable excipients inappropriate amounts for use in the invention. In addition, there are anumber of resources that are available to the skilled artisan whichdescribe pharmaceutically acceptable excipients and may be useful inselecting suitable pharmaceutically acceptable excipients. Examplesinclude Remington's Pharmaceutical Sciences (Mack Publishing Company),The Handbook of Pharmaceutical Additives (Gower Publishing Limited), andThe Handbook of Pharmaceutical Excipients (the American PharmaceuticalAssociation and the Pharmaceutical Press).

The pharmaceutical compositions of the invention are prepared usingtechniques and methods known to those skilled in the art. Some of themethods commonly used in the art are described in Remington'sPharmaceutical Sciences (Mack Publishing Company).

In one aspect, the invention is directed to a solid oral dosage formsuch as a tablet or capsule comprising a therapeutically effectiveamount of a compound of the invention and a diluent or filler. Suitablediluents and fillers include lactose, sucrose, dextrose, mannitol,sorbitol, starch (e.g. corn starch, potato starch, and pre-gelatinizedstarch), cellulose and its derivatives (e.g. microcrystallinecellulose), calcium sulfate, and dibasic calcium phosphate. The oralsolid dosage form may further comprise a binder. Suitable bindersinclude starch (e.g. corn starch, potato starch, and pre-gelatinizedstarch), gelatin, acacia, sodium alginate, alginic acid, tragacanth,guar gum, povidone, and cellulose and its derivatives (e.g.microcrystalline cellulose). The oral solid dosage form may furthercomprise a disintegrant. Suitable disintegrants include crospovidone,sodium starch glycolate, croscarmellose, alginic acid, and sodiumcarboxymethyl cellulose. The oral solid dosage form may further comprisea lubricant. Suitable lubricants include stearic acid, magnesiumstearate, calcium stearate, and talc.

In certain embodiment, the present invention is directed to apharmaceutical composition comprising 0.01 to 1000 mg of one or morecompounds of the above referenced formulas described herein or apharmaceutically acceptable salt thereof and 0.01 to 5 g of one or morepharmaceutically acceptable excipients.

In another embodiment, the present invention is directed apharmaceutical composition for the treatment of neurodegenerationdisease comprising a compound described herein or a pharmaceuticallyacceptable salt thereof.

What is claimed is:
 1. A compound of Formula (I-3) or a pharmaceuticallyacceptable salt thereof:

wherein R¹ is selected from the group consisting of H, C₁₋₃alkyl and—C(O)—C₁₋₃alkyl; and R² and R³ together with the carbon to which theyare attached form a 4, 5 or 6 membered saturated ring, which ringoptionally contains one heteroatom ring member selected from N or O, andis optionally substituted with one substituent of -L-K, wherein L isselected from the group consisting of C(O), CH₂, and S(O)₂, and K isselected from the group consisting of C₁₋₃alkyl, phenyl, andC₃₋₆cycloalkyl; or R¹ and R² together with the nitrogen and carbon towhich they are attached form a 5-membered saturated heterocyclic ring,which ring optionally contains one or two additional heteroatom ringmember independently selected from the group consisting of N, O, C(O),S, S(O), and S(O)₂, and is optionally substituted with one or moresubstituents independently selected from the group consisting of OH,halo, NR^(1a)R^(1b), COOH, and —Y—R^(c), wherein Y is absent or isselected from the group consisting of C(O), S(O)₂, —C(O)—C(O)—, and CH₂,and R^(c) is selected from the group consisting of C₁₋₅alkyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of NR^(2a)R^(2b), C₃₋₆ cycloalkyl, and —COOH,C₁₋₃haloalkyl, C₁₋₃alkoxyl, NR^(3a)R^(3b), —(CH₂)_(p)—C(O)—O—C₁₋₃alkyl,wherein p is 1, 2, or 3 and the —(CH₂)_(p)— is optionally substituted byone or more methyl, —(CH₂)_(q)—C₃₋₆ cycloalkyl wherein q is 1, 2, or 3,the cycloalkyl is optionally substituted with NR^(4a)R^(4b), and the—(CH₂)_(q)— is optionally substituted by one or more methyl, andheterocyclyl optionally substituted with one or more substituentsindependently selected from the group consisting of halo andNR^(5a)R^(5b), wherein R^(1a), R^(1b), R^(2a), R^(2b), R^(3a), R^(3b),R^(4a), R^(4b), R^(5a), and R^(5b) are independently H or C₁₋₃alkyl; andR³ is H; each occurrence of R⁴ is independently H or D; X is absent oris selected from the group consisting of —O—, —NH—, and —N (C₁₋₃alkyl)-, n is 1 or 2; or X is —O—CH₂— bicyclo[1.1.1]pentanyl-CH₂—O— andn is 0; A is

wherein R⁵ and R⁹ are independently H or halo, Z′ is N or CR⁶, Z is N orCR⁸, wherein R⁶ and R⁸ are independently selected from the groupconsisting of H, CN, halo, C₁₋₃alkyl, C₁₋₃haloalkyl, —S(O)₂—C₁₋₃alkyland —S(O)—C₁₋₃alkyl, and V is CR⁷, wherein R⁷ is -Q-(CH₂)_(m)—W, whereinQ is O, N, or CH₂, m is 0 or 1, and W is 6 membered heteroaryl, whereinthe 6 membered heteroaryl is selected from the group consisting ofpyridazinyl, pyrimidinyl, pyrazinyl, and triaziny, and wherein saidheteroaryl is optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₃haloalkyl, CN,halo and C₁₋₅alkyl.
 2. The compound or a pharmaceutically acceptablesalt thereof according to claim 1, wherein R¹ and R² together with thenitrogen and carbon to which they are attached form a 5-memberedsaturated, unsubstituted ring, which ring optionally contains oneadditional heteroatom ring member selected from N, O and C(O); and R³ isH; R⁴ is H; X is O; n is 1 or 2; and A is

wherein R⁵ and R⁹ are independently H or halo, Z′ is N or CR⁶, Z is N orCR⁸, wherein R⁶ and R⁸ are independently selected from the groupconsisting of H, CN, halo, C₁₋₃alkyl, C₁₋₃haloalkyl, —S(O)₂—C₁₋₃alkyland —S(O)—C₁₋₃alkyl, and V is CR⁷, wherein R⁷ is -Q-(CH₂)_(m)—W, whereinQ is O, N, or CH₂, m is 0 or 1, and W is 6 membered heteroaryl, whereinthe 6 membered heteroaryl is selected from the group consisting ofpyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
 3. The compound or apharmaceutically acceptable salt thereof according to claim 1, whereinR¹ and R² together with the nitrogen and carbon to which they areattached form a 5-membered saturated ring, which ring optionallycontains one additional heteroatom ring member selected from N, O andC(O), and R³ is H.
 4. The compound or a pharmaceutically acceptable saltthereof according to claim 1, wherein R¹ and R² together with thenitrogen and carbon to which they are attached form a 5 memberedunsubstituted, saturated heterocycle, which contains no additionalheteroatom ring member, and R³ is H.
 5. The compound or apharmaceutically acceptable salt thereof according to claim 1, whereinR⁴ is H.
 6. The compound or a pharmaceutically acceptable salt thereofaccording to claim 1, wherein X is O.
 7. The compound or apharmaceutically acceptable salt thereof according to claim 1, wherein nis
 1. 8. The compound or a pharmaceutically acceptable salt thereofaccording to claim 1, wherein A is

wherein R⁵ and R⁹ are independently H or F, and R⁶ and R⁸ areindependently selected from the group consisting of H, CN, and F, and R⁷is —O—W, wherein W is 6 membered heteroaryl, wherein the 6 memberedheteroaryl is selected from the group consisting of pyridazinyl,pyrimidinyl, pyrazinyl, and triazinyl, and wherein said heteroaryl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁₋₃haloalkyl, CN, halo and C₁₋₅alkyl.
 9. The compound or a pharmaceutically acceptable salt thereofaccording to claim 1, wherein A is

wherein R⁵ and R⁹ are independently H or F, and R⁶ and R⁸ areindependently selected from the group consisting of H, CN, and F, and R⁷is —O—W, wherein W is primidinyl, wherein said pyrimidinyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of CF₃ and CH₃.
 10. The compound orpharmaceutically acceptable salts thereof according to claim 1 has thefollowing structure:

wherein R¹ and R² together with the nitrogen and carbon to which theyare attached form a 5-membered saturated ring, which ring optionallycontains one additional heteroatom ring member selected from the groupconsisting of N, O, and C(O), and which ring has no furthersubstitution; R⁵ and R⁹ are independently H or F; R⁶ and R⁸ areindependently selected from the group consisting of H or F; and W¹ isprimidinyl, wherein said pyrimidinyl is optionally substituted with oneor more substituents independently selected from the group consisting ofCF₃ and CH₃.
 11. A compound or a pharmaceutically acceptable saltthereof has the structure of Formula (I-4)

wherein R¹ is selected from the group consisting of H, C₁₋₃alkyl and—C(O)—C₁₋₃alkyl; and R² and R³ together with the carbon to which theyare attached form a 4, 5 or 6 membered saturated ring, which ringoptionally contains one heteroatom ring member selected from N or O, andis optionally substituted with one substituent of -L-K, wherein L isselected from the group consisting of C(O), CH₂, and S(O)₂, and K isselected from the group consisting of C₁₋₃alkyl, phenyl, andC₃₋₆cycloalkyl; or R¹ and R² together with the nitrogen and carbon towhich they are attached form a 6-membered saturated ring, which ringoptionally contains one or two additional heteroatom ring memberindependently selected from the group consisting of N, O, C(O), S, S(O),and S(O)₂, and is optionally substituted with one or more substituentsindependently selected from the group consisting of OH, halo,NR^(1a)R^(1b), COOH, and —Y—R^(c), wherein Y is absent or is selectedfrom the group consisting of C(O), S(O)₂, —C(O)—C(O)—, and CH₂, andR^(c) is selected from the group consisting of C₁₋₅alkyl optionallysubstituted with one or more substituents independently selected fromthe group consisting of NR^(2a)R^(2b), C₃₋₆ cycloalkyl, and —COOH,C₁₋₃haloalkyl, C₁₋₃alkoxyl, NR^(3a)R^(3b), —(CH₂)_(p)—C(O)—O—C₁₋₃alkyl,wherein p is 1, 2, or 3 and the —(CH₂)_(p)— is optionally substituted byone or more methyl, —(CH₂)_(q)—C₃₋₆ cycloalkyl, wherein q is 1, 2, or 3,the cycloalkyl is optionally substituted with NR^(4a)R^(4b), and the—(CH₂)_(q)— is optionally substituted by one or more methyl, andheterocyclyl optionally substituted with one or more substituentsindependently selected from the group consisting of halo andNR^(5a)R^(5b), wherein R^(1a), R^(1b), R^(2a), R^(2b), R^(3a), R^(3b),R^(4a), R^(4b), R^(5a), and R^(5b) are independently H or C₁₋₃alkyl; andR³ is H; each occurrence of R⁴ is independently H or D; X is absent oris selected from the group consisting of —O—, —NH—, and —N (C₁₋₃alkyl)-, n is 1 or 2; or X is —O—CH₂— bicyclo[1.1.1]pentanyl-CH₂—O— andn is 0; and A is unsubstituted thiophenyl, or A is

wherein R⁵ and R⁹ are independently H or halo, Z′ is N or CR⁶, Z is N orCR⁸, wherein R⁶ and R⁸ are independently selected from the groupconsisting of H, CN, halo, C₁₋₃alkyl, C₁₋₃haloalkyl, —S(O)₂—C₁₋₃alkyland —S(O)—C₁₋₃alkyl, and V is CR⁷, wherein R⁷ is -Q-(CH₂)_(m)—W, whereinQ is O, N, or CH₂, m is 0 or 1, and W is 6 membered heteroaryl, whereinthe 6 membered heteroaryl is selected from the group consisting ofpyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl, and wherein saidheteroaryl is optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₃haloalkyl, CN,halo and C₁₋₅ alkyl.
 12. The compound or a pharmaceutically acceptablesalt thereof according to claim 11, wherein R¹ and R² together with thenitrogen and carbon to which they are attached form a 6-memberedsaturated, unsubstituted ring, which ring contains one additionalheteroatom ring member selected from N, O and C(O); and R³ is H; R⁴ isH; X is O; n is 1 or 2; and A is

wherein R⁵ and R⁹ are independently H or halo, Z′ is N or CR⁶, Z is N orCR⁸, wherein R⁶ and R⁸ are independently selected from the groupconsisting of H, CN, halo, C₁₋₃alkyl, C₁₋₃haloalkyl, —S(O)₂—C₁₋₃alkyland —S(O)—C₁₋₃alkyl, and V is CR⁷, wherein R⁷ is -Q-(CH₂)_(m)—W, whereinQ is O, N, or CH₂, m is 0 or 1, and W is 6 membered heteroaryl, whereinthe 6 membered heteroaryl is selected from the group consisting ofpyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl, and wherein saidheteroaryl is optionally substituted with one or more substituentsindependently selected from the group consisting of C₁₋₃haloalkyl, CN,halo and C₁₋₅ alkyl.
 13. The compound or a pharmaceutically acceptablesalt thereof according to claim 11, wherein R¹ and R² together with thenitrogen and carbon to which they are attached form a 6-memberedsaturated ring, which ring optionally contains one additional heteroatomring member selected from N, O and C(O), and R³ is H.
 14. The compoundor a pharmaceutically acceptable salt thereof according to claim 11,wherein R⁴ is H.
 15. The compound or a pharmaceutically acceptable saltthereof according to claim 11, wherein X is O.
 16. The compound or apharmaceutically acceptable salt thereof according to claim 11, whereinn is
 1. 17. The compound or a pharmaceutically acceptable salt thereofaccording to claim 11, wherein A is

wherein R⁵ and R⁹ are independently H or F, and R⁶ and R⁸ areindependently selected from the group consisting of H, CN, and F, and R⁷is —O—W, wherein W is 6 membered heteroaryl, wherein the 6 memberedheteroaryl is selected from the group consisting of pyridazinyl,pyrimidinyl, pyrazinyl, and triazinyl, and wherein said heteroaryl isoptionally substituted with one or more substituents independentlyselected from the group consisting of C₁₋₃haloalkyl, CN, halo and C₁₋₅alkyl.
 18. The compound or a pharmaceutically acceptable salt thereofaccording to claim 11, wherein A is

wherein R⁵ and R⁹ are independently H or F, and R⁶ and R⁸ areindependently selected from the group consisting of H, CN, and F, and R⁷is —O—W, wherein W is primidinyl, wherein said pyrimidinyl is optionallysubstituted with one or more substituents independently selected fromthe group consisting of CF₃ and CH₃.
 19. The compound or apharmaceutically acceptable salt thereof according to claim 11 isFormula (A-4),

wherein R¹ and R² together with the nitrogen and carbon to which theyare attached form a 6-membered saturated ring, which ring contains oneadditional heteroatom ring member selected from the group consisting ofN, O, and C(O), and which ring has no further substitution; R⁵ and R⁹are independently H or F; R⁶ and R⁸ are independently selected from thegroup consisting of H or F; and W¹ is pyrimidinyl, wherein saidpyrimidinyl is optionally substituted with one or two substituentsindependently selected from the group consisting of CF₃ and CH₃.
 20. Thecompound or a pharmaceutically acceptable salt thereof according toclaim 11 is Formula (A-5),

wherein R¹ and R² together with the nitrogen and carbon to which theyare attached form a 6-membered saturated ring, which ring contains oneadditional heteroatom ring member selected from the group consisting ofO and which ring has no further substitution; R⁵ and R⁹ areindependently H or F; R⁶ and R⁸ are independently selected from thegroup consisting of H or F; and W¹ is primidinyl, wherein saidpyrimidinyl is optionally substituted with one or two substituentsindependently selected from the group consisting of CF₃ and CH₃.
 21. Apharmaceutical composition comprising the compound or a pharmaceuticallyacceptable salt thereof according to claim 1, and a pharmaceuticallyacceptable excipient.
 22. A method for treating neurodegenerationdisease in a subject in need thereof comprising administering to thesubject a therapeutically effective amount of the compound or apharmaceutically acceptable salt thereof according to claim
 1. 23. Themethod according to claim 22, wherein the neurodegeneration disease isAlzheimer's disease.
 24. A method for treating atherosclerosis in asubject in need thereof comprising administering to the subject atherapeutically effective amount of the compound or a pharmaceuticallyacceptable salt thereof according to claim
 1. 25. A pharmaceuticalcomposition comprising the compound or a pharmaceutically acceptablesalt thereof according to claim 11, and a pharmaceutically acceptableexcipient.
 26. A method for treating neurodegeneration disease in asubject in need thereof comprising administering to the subject atherapeutically effective amount of the compound or a pharmaceuticallyacceptable salt thereof according to claim
 11. 27. The method accordingto claim 26, wherein the neurodegeneration disease is Alzheimer'sdisease.
 28. A method for treating atherosclerosis in a subject in needthereof comprising administering to the subject a therapeuticallyeffective amount of the compound or a pharmaceutically acceptable saltthereof according to claim 11.